Nanotechnology in healthcare, and its safety and environmental risks

1Nanomaterials are defined as materials that possess one or more peripheral nanoscale dimensions (in the range 1–100 nm). Nanotechnology, the field dedicated to the science and applications of these nanomaterials, is experiencing rapid and continuous growth. At this scale, the properties of materials undergo significant alterations. Characteristics such as solubility, reactivity, spectroscopy, electrical and magnetic attributes, as well as membrane transport, typically diverge from those exhibited by the same materials at larger scales. The unique properties exhibited by nanomaterials open up avenues for diverse applications and hold great promise for transformative advancements in various scientific and technological domains.

2In recent years, nanotechnology has emerged as a transformative force in the field of healthcare, offering continued innovation in medicine development and unprecedented possibilities for enhancing the performance and applications of medical devices. The ability to manipulate matter at the nanoscale has paved the way for groundbreaking innovations, promising revolutionary breakthroughs in diagnostics, treatment modalities, and overall patient care. Specific areas demonstrating the potential of nanotechnology in healthcare include medical diagnostics, where nanomaterials are used to improve the sensitivity and accuracy of imaging and biosensing techniques, enabling earlier and more precise detection of diseases. In tissue engineering, nanomaterials enhance cell interactions and tissue regeneration, offering promising advancements in areas like neural, dental, bone, and skin repair. Furthermore, nanomaterials are being developed for drug and gene delivery systems, where their ability to target specific cells or tissues can significantly enhance the efficacy of treatments while minimising side effects. In cancer therapies, nanomaterials can enhance the efficacy of traditional treatments such as surgery, radiotherapy, and chemotherapy, while also enabling the development of novel therapeutic approaches including biotherapy, photothermal therapy, and photodynamic therapy. Additionally, nanomaterials are being employed in antimicrobial and antiviral applications, including the creation of coatings and materials that can prevent infections and combat resistant pathogens.

3Despite the immense potential, however, the current application of nanotechnology in medicines and medical devices faces substantial challenges, both of a technical nature and within the complex realm of regulatory policies. This review aims to provide a comprehensive overview of the present status of nanotechnology in the medical domain, focusing on three critical dimensions: clinical applications, safety and environmental considerations, and the global regulatory landscape. By delving into the intricacies of these key aspects, we seek to elucidate the current achievements, gaps, and hurdles in the integration of nanotechnology into medicines and medical devices. Our exploration will shed light on the diverse facets of this dynamic field, addressing the promising clinical advancements, potential safety concerns, and the evolving regulatory frameworks that shape the landscape of nanotechnology in healthcare.

4Nanomaterials can be categorised into four primary types based on the degree of spatial confinement (Fig. 1). These include (i) zero-dimensional nanomaterials, where all dimensions are on the nanometer scale (e.g., nanoparticles), (ii) one-dimensional nanomaterials, where any one of the three dimensions is in the nanometer range (e.g., nanorods, nanowires, etc.), (iii) two-dimensional nanomaterials, where any two of the three dimensions are nanometer-sized (e.g., nanosheets, nanoplates, and nanocoatings), and (iv) three-dimensional nanomaterials, with each dimension in nanometer scale, thus allowing electrons to move freely without being confined in any direction. Examples include nanoflowers, nanocubes, nanocages, nanowire bundles, and various self-assemblies of lower-dimensional nanomaterials.

5In addition to spatial confinement, nanomaterials can also be classified based on origin, porosity, phase and dispersion. The multitude of classifications reflects the abundance of nanotechnology materials, which are playing an increasingly important role in healthcare applications. However, a more common method of classifying nanomaterials is based on their chemical composition. According to this, they can be classified into four material-based categories: organic-based, inorganic-based, carbon-based and composite-based nanomaterials (Fig. 1).

6Organic-based nanomaterials, which are formed via covalent or non-covalent assemblies of organic molecules, encompass a wide range of types used in healthcare applications, mainly including micelles, dendrimers, liposomes, nanogels, polymeric nanoparticles (NPs), extracellular vesicles, and nanoscale covalent-organic frameworks (COFs). The majority of them, with the exception of a limited number of modernist molecular machines, are polymeric in nature. These materials are highly regarded for their biocompatibility, making them ideal for in vivo applications, with certain types, such as aliphatic polyesters, being particularly renowned for their exceptional biodegradability. Additionally, organic-based nanomaterials can be easily functionalised, allowing for precise control over their chemical compositions, shape, size, and surface properties, making them highly adaptable to a variety of biomedical applications, such as bioimaging, drug delivery, and therapy (Fig. 2). For instance, semiconducting polymeric NPs are prized for their high extinction coefficients, photostability, and tunable emission profiles in the near-infrared (NIR) spectrum, making them ideal for deep-tissue imaging, including NIR-II fluorescence and photoacoustic imaging. Additionally, COFs have emerged as promising candidates in drug delivery and phototherapeutics due to their large porosity and superior photoelectric properties. Liposomes, vesicles, and micelles, which are extensively used for drug encapsulation, play a crucial role in minimising the off-target toxicity of potent therapeutic agents. The core composition, dimensions, and surface characteristics of these organic NPs are critical factors that determine their biocompatibility and functional efficacy in vivo.

7However, despite their advantages, organic-based nanomaterials also present certain limitations, including lower mechanical strength and stability compared to inorganic counterparts, which can restrict their use in applications requiring high structural integrity and thermal stability. Additionally, batch-to-batch variability in synthesis can affect reproducibility and scalability. Nonetheless, ongoing research aims to address these challenges, further enhancing the potential of organic nanomaterials in healthcare.

8Inorganic-based nanomaterials not only exhibit better chemical and mechanical stability compared to their organic counterparts, but also possess unique physicochemical advantages, such as optical, electrical, magnetic, ultrasonic, and catalytic properties. These advantages make them highly promising for biomedical applications, particularly in cancer imaging and therapy. However, their potential toxicity and poor biocompatibility, which can trigger adverse immune responses, induce inflammation, immunogenicity, and long-term toxicity, complicating their clinical translation. In addition, inorganic-based nanomaterials often suffer from limited biodegradability, leading to accumulation in tissues and organs, which can pose significant risks over extended periods. Nonetheless, progress in design and surface modification is steadily enhancing the safety and clinical potential of inorganic-based nanomaterials.

9Generally, inorganic-based nanomaterials in healthcare applications include different metal and metal oxide nanomaterials. Examples of metal-based inorganic nanomaterials are silver (Ag), gold (Au), aluminum (Al), cadmium (Cd), copper (Cu), iron (Fe), zinc (Zn), and lead (Pb) nanomaterials, whereas examples of metal oxide-based inorganic nanomaterials are zinc oxide (ZnO), copper oxide (CuO), magnesium aluminum oxide (MgAl2O4), TiO2, cerium oxide (CeO2), and iron oxide (Fe3O4), etc. Figure 2 highlights the advantages of metal and metal oxide NPs in healthcare applications. In addition, silicon-based nanomaterials, including porous silicon nanoparticles (pSiNPs), mesoporous silica nanoparticles (MSNs) and periodic mesoporous silica nanoparticles (PMONPs), have been intensively investigated for therapeutic and diagnostic applications. Moreover, layered double hydroxides (LDHs), metal carbides and nitrides (MXenes), and 2D transition metal borides (MBenes) are emerging as promising inorganic-based two-dimensional nanomaterials due to their exceptional surface area, tunable chemistry, and potential for drug delivery, biosensing, and theranostics.

10Carbon-based nanomaterials are considered as a separate class of nanomaterial with features such as diversity in their structures and facile functionalisation. Due to the unique properties, carbon can form covalent bonds with other carbons in different hybridisation states such as sp, sp2, and sp3 in order to form a variety of structures of small molecules and longer chains. Graphene (Gr), graphene oxide (GO), carbon nanotubes (CNTs), fullerenes (C60), carbon dots (CDs), graphene quantum dots (GQDs), carbon nanofibers (CFs), carbon onions, and carbon black are the different categories of carbon-based nanomaterials. These materials are highly valued in healthcare for their exceptional surface area, electrical conductivity, and mechanical strength. However, like inorganic nanomaterials, they face challenges in biocompatibility that need to be addressed. Their potential applications span drug delivery, bioimaging, tissue engineering, and diagnostic sensing.

11Composite-based nanomaterials, also known as hybrid nanomaterials, are any combination of metal-based, metal oxide-based, carbon-based, and/or organic-based nanomaterials, which often have complicated structures. Although many biomaterials use organic and inorganic materials individually, the increased demand for highly functionalised biomaterials has necessitated the development of organic/inorganic composite materials that not only integrate the advantages of each component, but also provide synergistic properties to meet new demands. For example, water non-dispersible inorganic NPs, such as gold nanoparticles (Au NPs), Fe3O4 NPs, semiconductor QDs, CDs, etc., can be rendered dispersible in water through surface modification with organic polymers like polyethylene glycol (PEG) or polydopamine (PDA). This modification enables precise control over their size, surface charge, and functionalisation, while maintaining desirable physical properties of the inorganic core such as magnetic, optical or catalytic activity. As a result, the presence of a organic polymer shell not only improves the dispersion of inorganic nanomaterials in biological fluids, but can also significantly enhance the biocompatibility of the inorganic core, acting as anchor sites for molecular linkages or protecting them from oxidation. Appropriately designed shell thicknesses can improve the chemical and thermal stability of NPs, while also regulating and controlling the release of molecules from the core.

12Such core–shell NPs have been widely investigated for cancer therapy, specific delivery of therapeutics, drug delivery monitoring, biosensors, bioimaging and antimicrobial activity. For example, a biosensor for detecting influenza A viral HA proteins (H1 and H5) was developed by modifying the surface of a field effect transistor (FET) with an aminooxy-terminated silane coupling reagent, highlighting the utility of surface-modified inorganic nanomaterials in biosensing applications. Moreover, A dual pH- and light-controlled drug delivery system was developed using surface-modified mesoporous silica NPs, demonstrating precise drug release and enhanced therapeutic efficacy in cancer treatment. Beyond surface modification, organic–inorganic NPs can be engineered through the self-assembly of block copolymers. Furthermore, inorganic NPs can be incorporated into polymer matrices to create bulk composite nanomaterials, such as functional hydrogels. A previous review provided a systematic analysis of hybrid nanomaterials.

13Another category of composite-based nanomaterials is metal–organic frameworks (MOFs), which are constructed from coordination bonds between metal-containing nodes and multidentate organic bridging ligands. MOFs offer customizable compositions and topologies, as well as high porosity and larger Brunauer–Emmett–Teller (BET) surface areas compared to single-component nanostructures. These properties make MOFs highly suitable for applications in cancer therapy, drug delivery, and bioimaging, positioning them as promising platforms in the field of biomedicine. For instance, a recently reported hierarchical and size-adaptable MOF nanovehicle was designed to effectively cross biological barriers at the tissue, cellular, and nuclear levels, enabling efficient nucleus-targeted delivery of doxorubicin (DOX). Additionally, a newly developed MOF/sulfonated hyaluronic acid composite coating was applied to the surface of magnesium alloy vascular stents, enhancing their biocompatibility and corrosion resistance, which is essential for improving the performance and longevity of vascular implants.

14Given their unique physicochemical properties, composite-based nanomaterials have become essential in advancing pharmaceuticals, targeted drug delivery, biosensors, medical imaging, and next-generation medical devices, driving innovation in more effective and personalised therapies.

15Nanotechnology has emerged as a promising field with significant potential for advancements in various healthcare and biomedical applications. Considering the extensive research conducted in this field and the numerous comprehensive reviews available, our focus will primarily be on providing concise descriptions of several mainstream applications of nanotechnology in recent years (Fig. 3).

16The progress of nanotechnology has significantly influenced the improvement of imaging techniques, early detection, diagnosis, and prognosis of diseases, enhancing existing clinically relevant technologies. The field of diagnostic sciences has incorporated nanodevices to achieve early and swift disease identification, leading to subsequent medical procedural recommendations. The potential of nanotechnology to transform healthcare diagnostics lies in its ability to enhance the precision, sensitivity, and speed of medical tests. One of the profound applications includes nanoparticle-based diagnostic imaging. The unique biophysical properties of NPs enable their attachment to specific biomarkers, thereby improving imaging modalities like magnetic resonance imaging (MRI), computed tomography (CT) scans, and positron emission tomography (PET) scans.

17MRI uses strong magnetic fields and radio waves to create detailed images of soft tissues by exploiting the behaviour of hydrogen atoms in the body. However, traditional MRI has limitations in contrast resolution, making it challenging to distinguish between different soft tissue types and detect small or early-stage lesions. Paramagnetic or superparamagnetic nanomaterials enhance MRI contrast by increasing interactions between water protons and paramagnetic centers, accelerating energy transfer and shortening spin–lattice (T1) or spin–spin (T2) relaxation times, thereby improving signal intensity and image clarity. These nanomaterials encompass paramagnetic complexes based on gadolinium (Gd) ions or manganese (Mn) ions, as well as superparamagnetic iron oxide NPs (SPIONs), all of which are widely used as contrast agents in MRI. Surface functionalisation can further improve their biocompatibility, prolongs circulation time, and enables targeted imaging, increasing both specificity and sensitivity. Recent advancements include the development of pH-activatable manganese carbonate (MnCO3) NPs that enhance T1-weighted MRI specifically in acidic tumour environments, significantly improving the ability to distinguish malignant from benign tissues and enabling more accurate detection of tumour malignancy and metastasis. Furthermore, a novel hypoxia-responsive tri-modal MRI nanoprobe (SPION@ND-IR780) encompassing T1, T2, and T2 mapping capabilities has been recently developed for enhanced imaging of hypoxic tumour regions in breast cancer. This nanoprobe undergoes structural transformations under hypoxic conditions, thereby significantly improving imaging accuracy and resolution. The precise visualisation of hypoxic areas facilitated by this system enables more targeted and effective radiotherapy interventions, addressing issues of tumour radioresistance (Fig. 4).

18CT imaging relies on X-ray attenuation to produce detailed images, making it crucial for diagnosing various medical conditions. Traditional small-molecule iodine-based contrast agents, such as iohexol and iodixanol, while effective, are constrained by rapid metabolic clearance, suboptimal targeting specificity, and the risk of adverse effects, including nephrotoxicity and allergic reactions, which limit their efficacy, especially in enhancing soft tissue contrast. Nanotechnology has introduced advanced contrast agents, including NPs like Au NPs, which offer improved stability, targeting, and biocompatibility. These nano-contrast agents can enhance imaging precision, reduce side effects, and improve the overall diagnostic capability of CT imaging by leveraging properties such as enhanced permeability and retention (EPR) and surface modifiability.

19For example, Au NPs functionalised with collagen-binding adhesion protein 35 (CNA35) have shown significant potential in improving CT imaging of myocardial scars. This approach allows for prolonged blood pool enhancement and specific targeting of collagen within scar tissue, providing clearer and more detailed images compared to conventional iodine-based agents. In a study involving a rat model of myocardial infarction, CNA35-conjugated AuNPs provided substantial signal enhancement in the scar tissue up to six hours post-injection, highlighting their potential for more precise cardiovascular diagnostics (Fig. 5).

20Additionally, a recent study introduced a novel self-assembled CT contrast agent, BioDHU-CT NPs, designed to leverage size aggregation for improved tumour imaging. They are composed of a biotin polyethylene glycol (Biotin-PEG) segment for hydrophilic properties and active targeting, an ROS-responsive group for rapid reactivity to reactive oxygen species, and an iodine-containing component modified with tetraphenylethene (TPE) for enhanced imaging capabilities. These NPs remain small for effective tumour penetration but rapidly aggregate upon activation by ROS in the tumour microenvironment. This size transformation enhances retention and extends the imaging window, significantly improving the contrast and clarity of tumour images in CT scans. The study demonstrated that these NPs provide more sustained and targeted imaging, offering a promising alternative to conventional contrast agents for tumour diagnostics.

21PET imaging is a diagnostic tool that enables the visualisation of metabolic processes within the body. By detecting pairs of gamma rays emitted indirectly by a positron-emitting radiotracer, PET provides detailed images of the function of tissues and organs. Nevertheless, traditional PET imaging faces certain limitations, including low spatial resolution and sensitivity, which hinder its ability to detect small or early-stage tumours. Moreover, the radiotracers commonly used in conventional PET tend to accumulate non-specifically in tissues, resulting in background noise that can obscure critical details.

22Similarly, PET imaging has seen significant advancements with the use of nanomaterials. NPs can be engineered to carry PET radiotracers, which accumulate in specific tissues, providing high-contrast images that are crucial for early detection of tumours and monitoring of metastatic spread. By addressing the limitations of traditional PET, NPs enable more precise and sensitive imaging. For instance, nanoscale MOFs have been developed that are intrinsically radioactive, such as the UiO-66 MOF radiolabeled with zirconium-89. It combines PET isotope zirconium-89 with 1,4-benzenedicarboxylate (BDC) and benzoic acid (BA) linkers, forming a highly porous structure. This porosity allows effective drug loading, while surface functionalisation with PEG and tumour-targeting peptides enhances stability, biocompatibility, and enables targeted imaging and drug delivery. In addition, nano-coordination polymers (NCPs) offer another promising example in PET imaging. Zr-P1 NCPs, composed of zirconium ions and tetrakis (4-carboxyphenyl)ethylene ligands, are radiolabeled with zirconium-89. Functionalised with PEG and cyclo(Arg-Gly-Asp-d-Phe-Cys) peptides, these NCPs target integrin αvβ3 in tumours, enhancing biocompatibility and specificity. This design improves PET imaging by reducing background noise and providing clearer, more precise tumour visualisation. Moreover, in the domain of single-cell tracking, radiolabeled NPs, such as 68Ga radioisotope labeled mesoporous silica NPs, have been used to track individual cancer cells though PET (Fig. 6). This technique helps study cell trafficking, immune cell movement in cancer immunotherapy, and cell distribution post-transplantation.

23Beyond these key medical imaging techniques (MRI, CT, and PET), nanomaterials are also being increasingly used in other advanced imaging modalities such as fluorescence imaging, photoacoustic imaging (PAI), and ultrasound imaging. A recent review provides a systematic study of nanomaterials used in these technologies, highlighting their potential to significantly enhance diagnostic precision and expand the capabilities of medical imaging. As research advances, these innovative nanomaterials are poised to revolutionise healthcare by enabling more accurate and personalised diagnostic solutions.

24Moreover, the impact of nanotechnology extends beyond imaging, notably enhancing the performance of biosensors. By increasing sensitivity and dramatically lowering detection limits by several orders of magnitude, nanomaterials facilitate the detection of trace biomolecules in bodily fluids such as blood and urine, which is critical for early diagnosis and effective disease management. These materials are integral in the immobilisation of biomolecules, signal amplification, and serving as mediators, electroactive species, and detection nanoprobes. Diverse nanomaterials, including NPs, nanowires, nanofilms, QDs, nanocrystals, nanorods, nanobelts, nanotubes, embedded nanostructures, and self-assembled nanomaterials, have been successfully integrated into biosensors. Their use is tailored to the specific conduction mechanisms of the biosensors, whether electrochemical, optical, or thermoelectric, further advancing the field of biomedical diagnostics and treatment strategies. The field is vast and continually evolving, with numerous studies and reviews offering more comprehensive insights into the latest developments.

25Tissue engineering combines biology, engineering, and materials science to develop substitutes that restore or enhance tissue function. This involves using scaffolds, cells, and bioactive molecules to create functional tissues for medical applications, aiming to repair damaged tissues and reduce the need for organ transplants. Key research areas include neural, dental, bone, and skin tissue engineering (Fig. 7) due to the high incidence of injuries and diseases affecting these tissues, as well as their complex structures and functions. These areas have significant clinical demand and potential for improving patients' quality of life. Advancements in nanotechnology have significantly improved therapeutic outcomes in these fields by enhancing biomaterials properties, cell interactions, and tissue regeneration processes.

26Neural engineering has benefited from the use of nanomaterials, demonstrating encouraging outcomes by facilitating cell adhesion and proliferation, and promoting neuronal cell differentiation, thus augmenting neuron regeneration. Currently, nanomaterials are expected to be used for the treatment of neurological injuries. Manipulation of the physicochemical properties of nanomaterials can prevent and/or treat neurodegeneration. For example, biodegradable natural polymers, SPIONs, carbon-based nanomaterials, and silica nanostructures have demonstrated exceptional properties and superior efficacy in facilitating neural cell differentiation and outgrowth. Composite-based nanomaterial of graphene and polyethylene terephthalate (PET) are employed in non-toxic, non-contact electrical stimulation to enhance cell-to-cell coupling in human neuroblastoma. Magnetic nanomaterials exploit magneto-responsive effects in response to an external magnetic field, allowing for the modulation of neuronal cell activity to either activate or inhibit, aiming to treat neurological diseases such as Alzheimer's disease and Parkinson's disease. In addition, studies have demonstrated the ability of metallic NPs like gold, iron, and cerium to ameliorate adverse pathological changes associated with spinal cord injury. Furthermore, innovative approaches using nanomaterials combined with other bioactive substances have shown synergistic effects in neural tissue engineering. Zhang et al. fabricated two piezoelectric polyvinylidene fluoride (PVDF) nanostripe array structures, with ridge, groove, and height dimensions of either 200 or 500 nm, designed as scaffold surfaces for neural tissue engineering. Their results revealed that the combination of piezoelectricity and nanogeometry favorably influenced neuron-like differentiation in both cell morphology and gene/protein expression, promising to promote nerve repair and regeneration (Fig. 8). In addition to the above, NPs can be functionalised to facilitate the crossing of the blood–brain barrier for targeted brain drug delivery.

27In conclusion, nanotechnology holds significant potential for indispensable applications in neural tissue engineering.

28Nanotechnology holds significant promise for advancing oral health in the field of craniofacial and dental tissue engineering, making it a prominent area for growth and potential enhancement of the quality of life of patients.

29The involvement of periodontal diseases in the hard and soft tissues surrounding the teeth results in gum diseases, bone loss, and, in more severe cases, tooth loss. Nanomaterials are expected to offer innovative, nonsurgical alternatives for addressing periodontal disease, exhibiting minimal side effects yet high efficiency. The post-subgingival injection of biodegradable polydopamine NPs has been shown to be capable of efficiently remove excessive reactive oxygen species (ROS) in vivo and decrease local periodontal inflammation. Au NPs with surface-anchored chiral amino acids (L-cysteine) have been reported to be able to regulate cellular behaviour through chiral effects and autophagy, thereby stimulating periodontal regeneration. In addition, lithiated porous silicon nanowires (LipSiNs) have been recently shown to combine osteogenic, cementogenic and Wnt/β-catenin stimuli, leading to the regeneration of bone, cementum, and periodontal ligament fibers in a murine model of periodontal defect (Fig. 9). This regenerative potential proved to be significantly higher compared to previously studied materials, including lithium chloride, porous silicon nanowires, lithium-substituted bioglass, and a commercial guided tissue regeneration membrane (GTR, BioGide®) used for the treatment of periodontitis.

30Oral and cranio-maxillofacial diseases are complications of the soft and hard tissues of the craniofacial, face and dental arches induced by physical, chemical, microbiological factors, and systemic disorders. These conditions include craniofacial defects and conditions such as head and neck tumours, craniosynostosis, dental implant failures, and osseous malunion. They often result in facial deformities and bone defects that require surgical intervention to correct normal facial features. Zirconium dioxide (ZrO2) NPs have been investigated for improving the mechanical properties and colour instability of maxillofacial prostheses such as silicone and silicone elastomers in order to enhance functionality and aesthetics. An electro-spun titanium oxide (TiO2)/hydroxyapatite (HA)/polyurethane (PU) nanocomposite fibre has been designed for use as an osseointegrated membrane to enhance new bone formation in oral and maxillofacial surgery.

31Furthermore, incorporating nanotechnology, specifically antibacterial NPs, into endodontic materials can enhance their properties, preventing recurrent infections and improving the success rates of root canal treatments. The incorporation of antimicrobial nano-coatings in orthodontic materials prevents the dental plaque formation around orthodontic appliances and prevents dental caries associated with orthodontic treatments. Nanomaterials like TiO2 nanotubes, silver nanoparticles (Ag NPs), and graphene oxide have been employed to coat the surface of titanium dental implants, aiming to improve osseointegration, soft tissue integration, immunomodulation, antitumour and antibacterial properties.

32Advances in nanomaterials, whether utilised independently or in conjunction with existing materials for oral medicine, offer innovative strategies for craniofacial and dental tissue engineering, thereby enhancing health, functionality, and aesthetics.

33Bone defects are the result of the compromised structural integrity of bones, primarily attributed to trauma and bone disease. The integration of nanotechnology into strategies for bone tissue engineering offers benefits by guiding cellular differentiation toward osteogenesis and aiding in the repair of substantial bone defects. NPs play a crucial role in advancing both scaffold-free and scaffold-based tissue engineering methods for promoting osteogenesis and bone regeneration. They modulate inflammatory responses and signaling pathways related to osteogenesis, angiogenesis, and osteoclast activity to create an osteogenic niche. Additionally, NPs interact with biomolecules, extending their half-life and enhancing bioavailability, making them highly promising materials for promoting osteogenesis. In bone tissue engineering, commonly used nanomaterials include metallic/metallic oxide NPs such as silver (Ag NP), strontium (Sr NP), magnesium oxide (MgO NP), cobalt ferrite (CoFe2O4 NP), among others. Additionally, calcium phosphate NPs including hydroxyapatite (HA) and tricalcium phosphate (TCP) are prevalent, alongside silicate-based NPs like bioactive silica-based glass particles (SBA2) and mesoporous silica NPs. Furthermore, polymeric NPs made of polymers such as poly(lactic acid) (PLA), poly(lactic acid) (PLA) nanofibers, poly(glycolic acid) (PGA), and poly(lactic-co-glycolide acid) (PLGA), chitosan, gelatin (Gel), and silk fibroin (SF) are commonly employed. For example, Sun et al. developed Gelatin Methacrylate (GelMA) hydrogels (CPP-L/GelMA) incorporating polymeric NPs to regulate the bone microenvironment by scavenging ROS and generating prolonged oxygen release. These NPs, serving as carriers of catalase (CAT) and oxygen, improved oxygen supply to the bone defect area, promoted angiogenesis and osteogenesis, inhibited osteoclastogenesis, and ultimately facilitated bone regeneration (Fig. 10).

34In addition, nano-surface modification of bone implants is widely adopted. Enhanced osteogenic capacity, modulation of macrophage-mediated inflammatory responses, and promotion of osteointegration are attainable through nano-surface modifications. Various techniques, such as acid etching, sandblasting, laser modification, anodisation, micro-arc oxidation, hydrothermal treatment, chemical vapor deposition (CVD), atomic layer deposition (ALD), plasma-immersion ion implantation (PIII), and lithography, have also been employed to modify the surface topography of grafts.

35These developments underscore the potential of nanomaterials to improve bone tissue engineering strategies, highlighting their promise in creating more effective bone repair solutions.

36Nanotechnology has been extensively studied in skin tissue engineering. The objective of skin tissue engineering is to rebuild both the structural and functional elements of skin, with the goal of minimising scar formation and enhancing the overall quality of wound healing. Clinical approaches of wound management include techniques like hyperbaric oxygen therapy, debridement, negative wound pressure therapy, and the use of wound dressings.

37Among these methods, the role of nanotechnology role is prominent in wound dressings. Nanocellulose, with its unique properties including enhanced absorbency and easier removal compared to traditional materials like gauze, is widely adopted in biomedical applications for treating skin diseases. Its nanoscale morphology mimics the native extracellular matrix, rendering it a favorable substrate for skin cell adhesion and growth. Combining nanocellulose with chitosan, poly (N-isopropylacrylamide) (PNIPAAm), polyvinyl alcohol (PVA), magnetic NPs, lactoferrin, collagen, and alginate in nanocomposites has demonstrated further improved effectiveness in repairing skin tissue.

38Autologous skin grafting is the “gold standard” of treatment for full-thickness injuries. However, due to the limitations of donor skin, the development of other tissue-engineered skin substitutes (such as skin regeneration scaffolds) is becoming increasingly important. Metal, ceramic and carbon-based nanomaterials have been introduced into scaffolds to reduce inflammation and enhance antimicrobial properties. Biomimicking scaffolds containing polymer nanofibres are able to recapitulate the native skin architecture and enhance cell proliferation. Additionally, dual-faced polymeric nanofibers, or Janus nanofibers, can be engineered to integrate various materials and functionalities, yielding synergistic physicochemical effects and presenting a promising material for skin tissue engineering. Zhou et al. introduced a self-pumping Janus dressing with dual layers to enhance wound exudate management and accelerate healing. This dressing consists of a hydrophobic drainage layer and a superabsorbent nanofiber layer, which work together to provide unidirectional fluid drainage and promote diabetic wound healing (Fig. 11).

39In summary, nanotechnology, through the development of advanced wound dressings and biomimetic scaffolds, plays a crucial role in enhancing skin tissue engineering by improving wound healing, minimising scarring, and supporting cell growth and proliferation.

40Nanotechnology has transformed the field of drug delivery by providing precise and efficient drug-targeted delivery, smart-responsive drug release, and extraordinary in vivo stability, resulting in improved therapeutic efficacy, higher bioavailability, and reduced side effects. A wide array of organic and inorganic nanomaterials has been developed to address various physicochemical challenges associated with drugs, including low solubility, stability, off-target deposition, and limited penetration across biological barriers.

41The efficacy of NPs as drug carriers varies depending on factors like their shape, size, and other inherent biophysical or chemical characteristics. Additionally, the method of drug loading, whether through conjugation or adsorption, plays a significant role in determining their performance. Conjugation involves the formation of covalent bonds between drug molecules and the surface of NPs, which can enhance drug stability, provide controlled release, and improve targeted delivery to specific tissues or cells. In contrast, adsorption relies on non-covalent interactions, such as hydrophobic interactions or electrostatic forces, to physically load drugs onto NPs. While this approach is more straightforward and cost-effective, it may offer less stability and control over drug release compared to conjugation.

42In nanomaterial drug delivery systems, the effectiveness of drug-targeted delivery can be further enhanced by employing both passive and active transport mechanisms, which complement the inherent characteristics of NPs as drug carriers. Passive drug transport leverages the physicochemical properties of the nanocarriers and the specific physiological environment of the target tissue. For instance, through the EPR effect, nanomedicines can passively accumulate at tumour sites, taking advantage of the leaky vasculature commonly found in tumours. In contrast, active drug transport involves more precise interactions between nanomedicines and specific cellular targets, such as ligand-receptor binding, pH-responsive release, or the use of cell-penetrating peptides, which enable the drugs to efficiently target and enter specific cells. These active mechanisms often work synergistically with passive transport to enhance the overall efficiency, specificity, and safety of drug delivery, particularly when combined with the strategic attachment methods of drug loading methods discussed earlier.

43Doxil®, approved by the United States Food and Drug Administration (FDA) in 1995, marked the formal introduction of nanoparticle-based drug delivery formulations into clinical use. Traditional nanomaterial drug delivery systems, represented by Doxil®, have successfully achieved drug targeting and improved bioavailability. However, challenges such as drug toxicity and long-term biosafety remain. Doxil® is a PEGylated liposomal formulation of doxorubicin that employs the EPR effect as a passive targeting mechanism, along with surface PEG modification. The hydrophilic PEG shell protects the drug from degradation by serum components and prevents opsonisation by the complement system, thereby avoiding rapid clearance by the mononuclear phagocytic system (MPS) and extending circulation time. While these modifications enhance bioavailability and drug delivery, the reliance on the passive EPR effect alone results in low targeting efficiency, which can still lead to significant cardiotoxicity, similar to that of the original DOX.

44To address the shortcomings, novel nanomaterial drug delivery platforms are being developed to achieve precise drug delivery by integrating both active and passive targeting mechanisms. This approach aims to reduce drug toxicity while enhancing therapeutic efficacy. Abraxane®, a nanoparticle-based formulation of paclitaxel bound to albumin, exemplifies this strategy and was approved by the FDA in 2005. Albumin, a natural blood protein, contains hydrophobic pockets that can bind paclitaxel through hydrophobic interactions. Serving as a natural carrier, albumin increases paclitaxel's solubility in the bloodstream and offers advantages such as biodegradability, non-toxicity, and non-immunogenicity. Tumour tissues overexpress secreted protein acidic and rich in cysteine (SPARC), which functions similarly to albumin receptors by selectively binding albumin and accumulating it in tumour cells. Additionally, the high demand for albumin in tumour tissues further facilitates the concentration of drug-loaded albumin NPs at the tumour site. These characteristics enable albumin-based nanoparticle formulations to significantly increase local drug concentrations in tumour tissues, thereby reducing systemic toxicity and improving patient tolerance.

45Additionally, numerous nanoparticle-based formulations that combine active and passive targeting mechanisms are currently undergoing clinical trials. For example, MBP-426 is a novel nano drug delivery system in which oxaliplatin is encapsulated within N-glutaryl phosphatidylethanolamine (NGPE) liposomes and bound to transferrin. Transferrin acts as a targeting carrier by binding to transferrin receptors, which are highly expressed in tumour tissues, thereby efficiently delivering the drug to cancer cells. Phase I clinical trials of MBP-426 have been completed, and the formulation has since advanced to a Phase Ib/II clinical trial in second-line patients with gastric, gastroesophageal, or esophageal adenocarcinoma.

46Recent studies have shown that molecularly imprinted polymeric nanoparticles (MIP NPs) are promising candidates for drug delivery systems that integrate both active and passive targeting mechanisms. MIP NPs have been designed with specific and complementary binding sites for drug molecules (referred to as “templates”) within their polymer matrix. These sites enable MIP NPs to recognise and load drugs or other templates with antibody-like affinity and selectivity, through either covalent or non-covalent binding. This ability allows MIP NPs to improve the precision of drug delivery and release. Furthermore, the development of dual-imprinted polymers enables both drug loading and in vivo targeting, facilitating active targeted delivery and responsive release of drugs. For example, Liu et al. developed a novel pH-responsive core–shell MIP NPs (FASC MIPs) for prostate cancer treatment. This formulation uses superparamagnetic tetraoxide NPs as the core material. The surface of these NPs was modified to create two types of imprinted cavities: one designed to sequester free testosterone (TETO) from solid tumours and another loaded with the anti-androgen drug bicalutamide (BIC). The NPs were further coated with pH-responsive chitosan, which facilitates targeted drug release in the acidic tumour microenvironment (Fig. 12). The FASC MIPs demonstrated synergistic antitumour effects by specifically targeting TETO through the imprinted cavities and releasing BIC in response to the acidic conditions, effectively inhibiting prostate cancer cells growth both in vitro and in vivo.

47Moreover, the high stability and robustness of MIP NPs protect the loaded drug molecules from complex biological environments, such as those in the gastrointestinal tract, making them suitable for various applications, including sustained transdermal formulations, therapeutic contact lenses, and oral formulations for protein delivery.

48Enhancing the drug solubility and increasing stimulus-responsive release have been shown to effectively improve passive and active transport, respectively. For example, Gou et al. developed carboxyl-functionalised mesoporous silica NPs (MSN-COOH) using a silicon coupling agent (hyd-TESPSA), which enhanced drug loading and solubility for poorly water-soluble non-steroidal antiinflammatory drugs (NSAIDs) like nimesulide and indomethacin. The MSN-COOH improved drug bioavailability and efficacy by converting the drugs to an amorphous state and enabling pH-responsive release, thereby enhancing passive diffusion and active targeting to specific tissues, which reduces side effects. In addition to pH-responsive formulations, temperature, light, magnetic, ultrasound, and electrical-responsive drug delivery systems are also being increasingly developed. An example of a light-responsive system is the use of black phosphorus (BP) nanosheets for targeted drug delivery. Jin et al. demonstrated that BP nanosheets, which possess excellent biodegradability and biocompatibility, can effectively load the antidepressant fluoxetine (Flu) through electrostatic interactions. Upon exposure to near-infrared (NIR) light, these BP-Flu composites facilitated a rapid and controlled release of Flu, significantly reducing treatment duration and minimising side effects associated with the free drug (Fig. 13).

49In summary, nanomaterial drug delivery systems can provide targeted drug delivery, enhance therapeutic efficacy, improve the solubility and bioavailability of challenging drugs, and reduce toxicity. By integrating both active and passive targeting mechanisms, these systems achieve greater precision and improved biological safety. Additionally, they allow for precise drug release in diseased areas through internal responses to physiological changes and external responses to stimuli like pH and light.

50In addition to strategies for precise drug release to targeted tissues, effectively penetrating various biological barriers is crucial for maximising the efficacy of nanoformulations. These barriers include distribution barriers, microenvironmental barriers, and cellular and intracellular barriers.

51First, optimising the route of administration can significantly influence nanomaterials distribution. For example, intravenously injected polymeric NPs, such as PLGA NPs, tend to accumulate in the liver and spleen, while subcutaneous or lymphatic administration directs them more effectively to local lymph nodes. Inhalation can deliver drugs directly to the lungs, bypassing systemic circulation and avoiding first-pass metabolism in the liver. For systemic delivery, modifying the NP surface, such as with PEGylation, can prolong circulation time and enhance drug exposure. Adjusting NP size is also critical (Fig. 14a: NPs smaller than 10 nm are quickly cleared by the kidneys, whereas those larger than 200 nm can trigger immune responses unless specifically engineered.

52After reaching the target site, nanomaterial drug delivery systems encounter diverse microenvironments distinct from the circulatory system, such as acidic and enzyme-rich conditions in the gastrointestinal tract, low pH and high permeability in tumour tissues, and pH fluctuations in wound healing. To overcome these challenges, NPs can be modified to respond to specific microenvironmental conditions. For example, pH-sensitive polymer coatings can enhance drug release in acidic environments, enzyme-resistant shells can protect NPs from degradation in the digestive tract, and penetration enhancers can improve NP delivery in tumour tissues. Dynamic response modifications allow NPs to adapt to changing conditions, further enhancing therapeutic outcomes.

53Modifying nano drug carriers can help them overcome cellular and intracellular barriers, ensuring effective drug delivery (Fig. 14b. Once inside the cell, NPs are often trapped in vesicles or endosomes, where the environment becomes increasingly acidic over time. To promote drug escape from the endosome, some NPs are designed to respond to acidic or reductive environments, such as through the proton sponge effect or cleavable linkers, helping them disrupt the endosomal membrane and release the drug. Additionally, complex-shaped NPs, such as nanostars, have shown promise in improving endosomal escape. Once in the cytoplasm, drugs may need to traverse further intracellular membranes to reach specific organelles like the nucleus or mitochondria. pH-responsive nanoparticle systems are particularly useful in targeting these regions, especially for applications in gene editing or cancer immunotherapy, as discussed further in the following sections.

54Expanding on drug delivery applications, these innovative nanoplatforms are now making significant strides in delivering gene therapeutics. Gene therapy is an experimental technique that exerts its therapeutic effects by introducing nucleic acids (DNA or RNA) into patient cells, enabling the expression of new genes or regulating the expression of target genes by correcting, disrupting or replacing them to prevent or treat a wide range of diseases. However, the effective in vivo delivery of nucleic acids into cells remains a significant challenge due to their low in vivo stability and susceptibility to rapid clearance from the bloodstream affecting their cellular uptake. Furthermore, nucleic acids have limited permeability through cell membranes owing to their electronegativity and large molecular size, posing a challenge to their effective cellular entry.

55Gene therapy can be stratified into DNA and mRNA-based therapy, with each encountering distinct challenges. In DNA-based therapies effective gene delivery involves overcoming extracellular barriers including enzymatic degradation and immune clearance, as well as intracellular barriers endosomal entrapment and nuclear transport across the nuclear envelope, a necessary step in DNA delivery and successful transgene expression. Similarly, mRNA-based therapies must maintain the stability of the mRNA amid nucleases within the extracellular environment and avoid clearance. Unlike DNA therapies, in mRNA-based therapies, translation occurs in the cytosol rather than the nucleus, making endosomal escape a key intracellular barrier to conquer. These challenges necessitate the development of vectors that can overcome extracellular and intracellular barriers to deliver genetic materials into target cells. Traditional vectors such as viral vectors are limited by obstacles such as immunogenicity, rapid clearance, limited genome packaging capacity, and potential carcinogenicity.

56Therefore, the ideal vector should protect genetic material, avoid clearance, enable cellular uptake, promote early endosomal escape, and be biocompatible, biodegradable, non-immunogenic and non-toxic to host cells. Thus, efforts have shifted towards non-viral vectors, such as NPs, which have emerged as powerful tools to overcome the challenges associated with viral vectors for gene delivery by enabling safe and efficient targeting. These NPs boast a high drug-loading capacity, low mutagenicity and the ability to overcome biological barriers without provoking immune responses (Fig. 15).

57Furthermore, NPs are hailed for their small size, high surface-to-volume ratio, and tunable properties that allow for selective targeting. Moreover, their ability to encapsulate genetic materials protects them from enzymatic digestion and facilitates efficient cellular uptake making them ideal vectors for gene delivery. This protective capacity is exemplified with lipid NPs which have gained particular attention, especially with the recent success of the mRNA COVID-19 vaccines like BNT162b2 (Comirnaty® by BioNTech and Pfizer) which demonstrated 95.0% effectiveness in preventing COVID-19. These lipid NPs protect the mRNA encoding the SARS-CoV-2 spike protein by encapsulating it into the core, ensuring its safe delivery into target cells where it can be translated and trigger an immune response.

58In addition to safeguarding genetic cargo, NPs must also facilitate cellular uptake and gene transfection, a process that can be hindered by the formation of a protein corona by serum proteins, leading to the physical destabilisation and agglomeration of NPs. Xiong et al. developed zwitterion CBAA-modified gold dendrimer-entrapped NPs (Au DENPs) for serum-enhanced gene delivery to address this. Remarkably, the zwitterion coating conferred the NPs with antifouling properties, resisting serum protein adsorption and increasing gene delivery efficiency between 1.4 to 1.7-fold in serum-containing media compared with serum-free medium (Fig. 16). Consequently, NPs endowed with anti-fouling properties effectively enhanced gene delivery by preventing serum adsorption, suggesting their potential to circumvent immune clearance.

59As previously discussed, DNA-based therapies require the DNA cargo to enter the nucleus for efficient transgene expression. However, once inside the cell, NPs delivering DNA encounter several significant obstacles involving escaping from endosomal compartments before lysosomal trafficking and nucleus translocation which involves crossing the nuclear envelope, a formidable barrier, for transcription. To overcome this, NPs have been designed with nuclear targeting capabilities and nuclear localisation signals to ensure gene delivery across the nuclear envelope. Wang et al. formulated pH-sensitive NPs delivering the CRISPR/Cas9 system and epirubicin to the nucleus in cancer cells (Fig. 17). These stimuli-responsive NPs exploit EGFR-targeting peptides and nucleus-localising sequences that enable endosomal escape and direct nuclear localisation under acidic tumour conditions. By exposing targeting peptides at a lower pH, cellular uptake and transfection efficiency were enhanced. This demonstrates the potential of NPs to successfully target and traverse the nuclear envelope resulting in efficient gene delivery.

60In conclusion, NPs are proving to be sophisticated vectors for overcoming key challenges in gene delivery. The development of these advanced nanomaterials has significantly enhanced the potential of gene delivery systems, offering solutions to the limitations of traditional viral vectors. The continued innovation in nanomaterial design and functionalisation is anticipated to result in more effective and safer gene delivery systems, ultimately enhancing therapeutic outcomes and broadening the scope of their applications.

61Cancer remains a prominent cause of mortality globally, with conventional approaches identified for tumour-specific treatment: surgical resection, chemotherapy, and radiation therapy. However, despite these treatment options, cancer patients often face short survival expectation and poor life quality.

62The rapid development of nanotechnology has introduced complementary and alternative strategies for cancer treatment by using both passive targeting, due to the small size of NPs, and active targeting, achieved through specific modifications to the NPs, thereby offering greater precision in therapy. As mentioned in Sect. “Drug delivery”, passive targeting of NPs takes advantage of the EPR effect, which occurs due to the abnormal structure of tumour blood vessels. These vessels have looser walls and inadequate lymphatic drainage, allowing macromolecules or NPs to penetrate and accumulate more easily within tumour tissues. Active targeting, in contrast, involves the surface modification of NPs with specific ligands such as antibodies, peptides, or carbohydrates that bind selectively to receptors on tumour cells (Fig. 18). This enhances the precision of drug delivery, exemplified by the use of trastuzumab, an antibody targeting the HER2 receptor, or folic acid ligands targeting the folate receptor.

63Modified NPs frequently combine both passive and active targeting mechanisms to effectively direct them to tumour tissues, addressing the limitations of traditional cancer therapies, such as limited efficacy, toxicity, severe side effects, cancer recurrence, and drug resistance. The following section explores the use of nanomaterials in surgical resection, radiation therapy, chemotherapy, and other novel therapies.

64Accurate detection of malignant and healthy tissues is crucial for the therapeutic efficacy of surgical resection. As described in Sect. “Medical diagnostics”, nanomaterials such as QDs, surface-enhanced Raman spectroscopy (SERS) NPs, luminescent NPs and dye nanoformulations, are able to act as contrast agents for image-guided surgery. These modified NPs differentiate between tumours and nearby normal tissues through active targeting and passive targeting effects, thus helping surgeons to identify surgical margins and local metastases with high resolution and sensitivity, leading to improved therapeutic outcomes (Fig. 19).

65In addition, many nanomaterials have been used to construct fast and efficient hemostatic measures that significantly improve safety during surgical treatments. After surgery, wound healing involves three primary stages to stop bleeding. First, the damaged blood vessels constrict to reduce blood flow. Next, platelets aggregate to form an initial platelet plug that seals the wound. Finally, the coagulation cascade activates, producing fibrin that combines with the platelet plug to form a stable clot, effectively preventing further blood loss. NPs have unique advantages in promoting hemostasis by enhancing platelet activation and aggregation, similar to platelet-activating factors. For example, Liang et al. synthesised zeolitic imidazolate framework (ZIF-8) nanoparticle-enhanced cryogels that provide rapid hemostasis during tumour resection surgery by promoting coagulation and stopping bleeding. Additionally, these cryogels help prevent cancer recurrence after liver cancer surgery by releasing drugs in response to pH changes and generating reactive oxygen species under ultrasound to kill remaining cancer cells.

66In radiation therapy, therapeutic effects often necessitate higher doses of irradiation, as tumour cells exhibit low radiation absorption. However, this can result in significant damage to surrounding normal tissues. Therefore, the development of radiosensitisers and methods to protect normal tissues is a major strategy to increase the sensitivity of tumours to radiation therapy and to minimise side effects. Nanomaterials that incorporate high atomic number elements, including Au-, gadolinium (Gd)-, bismuth (Bi)-, hafnium (Hf)- and tungsten (W)-based nanomaterials can increase intracellular radiation deposition, making them potentially ideal sensitisers for radiotherapy (Fig. 20).

67Targeted modifications can further increase intratumoural enrichment to absorb radiation energy and promote the efficacy of radiation therapy. Jyothi U et al. developed a novel nanoparticle system, R11-NU7441 NPs, which consists of PLGA NPs conjugated with the prostate cancer cell-penetrating peptide R11 and encapsulated with the potent radiosensitizer 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441). This system is designed for active targeting specifically to prostate cancer cells and provides a sustained release of NU7441, significantly enhancing the effectiveness of radiotherapy.

68In addition to radiosensitisation, inorganic-based nanomaterials, exemplified by wide-ranging oxides of cerium (Ce), manganese (Mn), tantalum (Ta), and vanadium (V), play an important role in radioprotection due to their excellent enzyme-mimicking properties and their ability to scavenge ROS generated by radiotherapy in normal tissues, thus potentially reducing radioinflammation.

69Conventional chemotherapeutic drugs typically lack specificity, causing potential damage to normal tissue cells alongside cancer cells during chemotherapy, resulting in severe adverse effects. Additionally, drug resistance and poor water solubility also hinder the effectiveness of chemotherapy drugs in clinical use. As detailed in Sect. “Drug delivery”, NPs transport chemotherapeutic drugs to the tumour site by direct targeting through chemical modification or passive targeting of tumour cells through the EPR effect, thereby reducing systemic toxicity. Moreover, nanocarriers can effectively address issues such as poor solubility, rapid metabolism, unstable absorption, insufficient permeability, and drug resistance associated with small molecule drugs.

70Expanding on traditional treatments, advancements in tumour understanding have spurred rapid development in new therapeutic approaches such as biotherapy (including cellular immunotherapy, gene therapy, etc.), photothermal therapy (PTT), and photodynamic therapy (PDT). Some examples are shown in Fig. 21.

71These emerging methods significantly enhance comprehensive tumour treatment, improving patient prognosis and quality of life. PTT and PDT offer safety, non-invasiveness, and high efficiency. Yet, traditional photosensitisers lack specificity and suffer from low water solubility, limiting their bioavailability. Nanocarriers boost photosensitiser accumulation in tumours, enhancing phototherapy effectiveness while minimising damage to healthy tissues.

72While immunotherapy is esteemed, it encounters challenges like low patient responsiveness, limited tumour specificity, and immunosuppressive tumour microenvironments. Nanomaterial-based approaches, such as inducing immunogenic cell death (ICD), combining with immune checkpoint blockade therapy, cancer vaccines, adoptive immunotherapy, and immune microenvironment modulation, show promise in enhancing tumour immunotherapy efficacy.

73Gene therapy introduces genes into cells to correct abnormalities and produce therapeutic proteins. It sidesteps the systemic toxicity and tolerance issues typical of chemotherapy. The development of gene therapy relies heavily on nanotechnologies. As mentioned in Sect. “Gene delivery”, gold, polymer, and lipid NPs are amongst the main non-viral carriers for gene delivery, which can effectively deliver small molecules of nucleic acids, prevent their extracellular degradation by nuclease and improve drug distribution. In conclusion, nanotechnology plays a vital role in numerous cancer treatments.

74Nanotechnology is essential in many cancer treatments; however, NPs face challenges in tumour therapy due to individual heterogeneity among patients. The primary advantage of NPs in cancer therapy is their ability to specifically accumulate in tumour tissues through passive and active targeting mechanisms. Passive targeting largely relies on the EPR effect, but this effect is significantly influenced by various factors. Different tumour types, such as solid tumours like breast cancer and pancreatic cancer, may show a more pronounced EPR effect, while blood tumours or tumours with poor vascularsation may demonstrate a weaker EPR effect. The uneven angiogenesis of tumours, depending on their anatomical location and vascular characteristics, can also impact the EPR effect, particularly in tumours that are less vascularised or have poor vascular permeability. Additionally, the diverse microenvironments of tumours, characterised by different pressure states and compositions, affect the efficacy of the EPR effect and consequently the accumulation of NPs in tumour tissues. Furthermore, individual patient differences, such as variations in physiological state, hemodynamic characteristics, inflammation levels, and vascular permeability, contribute to the variability in the EPR effect.

75To address the challenges posed by this individual heterogeneity and reduced targeting effectiveness, several strategies have been proposed. These include personalised treatment plans that assess each patient's tumour vascularisation and microenvironment characteristics to develop tailored NP delivery strategies, combination therapies that integrate both EPR and active targeting strategies to enhance the accumulation of NPs in tumours, and auxiliary methods such as using ultrasound or vascular permeability enhancers to boost the EPR effect in tumour tissues. These strategies aim to overcome the limitations of individual differences and optimise the therapeutic potential of NPs in cancer treatment.

76Overuse or misuse of conventional antibiotics in various sectors such as medical care, livestock farming, and agriculture has resulted in heightened antibiotic resistance, diminished efficacy of antibiotic therapies, and the rise of superbugs. This resistance develops when bacteria adapt to survive antibiotics, often through mechanisms such as modifying target sites, producing enzymes that deactivate antibiotics, using efflux pumps to expel the drugs, reducing membrane permeability to prevent antibiotic entry, or forming protective biofilms that blocks antimicrobials penetration. These adaptations not only complicate infection management but also contribute to higher mortality rates, prolonged hospital stays, and the need for more expensive and potentially toxic alternative therapies. Given the limitations of traditional antibiotics in overcoming these resistance mechanisms, there is an urgent need for innovative antimicrobial strategies.

77Advances in nanotechnology present hopeful avenues for addressing these challenges. Nanomaterials enable deliberate engineering designs, including size control, surface modification, crystalloid change, and stimuli-responsive functionalisation, which offer unique interactions with bacterial cells compared to conventional antibiotics. Such interactions frequently lead to distinctive killing mechanisms and exceptional antimicrobial attributes, including broad-spectrum activity, long-lasting effects, inhibition of biofilm formation and resistance-independent antimicrobial effects. By circumventing traditional pathways of resistance, nanotechnology-based solutions have the potential to revolutionise the fight against resistance, offering new hope for effective and sustainable antimicrobial therapies.

78Five classes of antimicrobial nanomaterials have been extensively researched and reported, encompassing metallic NPs (such as Ag, Cu, Au, ZnO, La2O3, CeO2, V2O5, etc.), carbon-based nanomaterials (including graphene, GO, CNTs), borides (like boron nitride), nanosized polymers (such as polycarbonate), and nanocomposites (for instance, La2O3/Ag-GO). Based on the initial interactions between the materials and bacteria, Xie et al. proposed a summary of several antimicrobial mechanisms, including membrane destruction, disruption of the electron transport chain, catalytic killing, cell division arrest, cell trapping, and ionic killing (Fig. 22a–f). In addition, they proposed four design principles for fabricating antimicrobial nanomaterials to prevent the resistance evolution include: engineering nanocomposites to diversify nano-microbe interactions, enabling stimuli-responsive functionalisation for controllable bactericidal effects, grafting targeting ligands for precise bacterial killing, and incorporating doping/shielding to prevent triggering defense mechanism in bacterial cells due to the release of metal ions (Fig. 22g).

79In addition to directly targeting bacteria, nanomaterials can combat antimicrobial resistance (AMR) by targeting bacterial biofilms through various mechanisms. Biofilms, protective layers formed by bacterial communities, are significant contributors to chronic infections and increased antibiotic resistance, particularly in the case of multi-drug resistant (MDR) infections, where bacteria are resistant to multiple antibiotics. These structured communities of bacteria are encased in a self-produced extracellular polymeric substance (EPS) that protects them from external threats, including antibiotics, thereby complicating treatment efforts. Therefore, strategies that enhance the penetration of antimicrobials into biofilms, disrupt mature biofilms, and prevent biofilm formation are crucial for effectively combating the development of AMR and MDR infections.

80By modulating the size, shape, and surface properties of NPs, it is possible to enhance their penetration into biofilms, thereby weakening the protective barrier provided by the biofilm. For instance, while EPS can inhibit the penetration of silver ions, Ag NPs with diameters less than 20 nm can effectively penetrate biofilms of Escherichia coli and Pseudomonas fluorescens.

81Nanomaterials can also disrupt mature biofilms. NPs with unique shapes, such as nanosheets, nanoneedles, and sea urchin-shaped NPs, can mechanically disrupt the EPS of biofilms. Magnetic nanomaterials have been shown to cause mechanical disruption of biofilms through the application of direct and alternating magnetic fields. For example, a magnetic urchin-like capsule robots (MUCRs) developed by Sun et al. loaded with magnetic liquid metal droplets (MLMDs) can change shape into spheroids and rods with sharp edges when triggered by an external magnetic field. These sharp edges, along with natural microspikes, can physically disrupt the protective function and mechanical stability of EPS (Fig. 23). Additionally, the applied mechanical force can break bacterial cells embedded within the biofilm, contributing to the overall destruction of the biofilm.

82Beyond mechanical damage, electron transfer can also be used to disrupt biofilms. 2D transition metal disulfide (MoS2) nanosheets with nanoholes containing atomic vacancies can enhance electron transport interactions with biofilms, disrupting key components of mature biofilms such as proteins, polysaccharide intercellular adhesin (PIA), and extracellular DNA, while downregulating the expression of related genes. Moreover, oxidative stress can not only damage bacterial cell membranes but also lead to the degradation of EPS, achieving a synergistic antibacterial and anti-biofilm effect. Various advanced nanomaterials have been reported to generate ROS and reactive nitrogen species (RNS) through different mechanisms, including photocatalysis, nanozyme catalysis, photodynamic therapy, sonodynamic therapy, and nitric oxide (NO) therapy. For example, in a recent study supramolecular photosensitiser NPs were developed, capable of producing ROS under light irradiation to disrupt biofilms and release antibiotics, effectively combating MDR bacteria by breaking down the biofilm structure and enhancing drug penetration. Another example is a polymeric NPs internally loaded with the photosensitiser chlorin e6 designed for root canal irrigation, which combines photodynamic therapy with NO release. This system enhances biofilm penetration and eradication by generating ROS and NO simultaneously, providing an effective strategy against endodontic bacterial infections, especially in the treatment of apical periodontitis.

83Certain nanomaterials do not combat bacteria and biofilm through direct interaction but instead inhibit biofilm formation and virulence expression by disrupting bacterial quorum sensing (QS) systems, the process by which bacteria communicate with each other. This approach is expected to reduce the risk of developing resistance by avoiding selection pressure on bacteria. In addition, since QS systems are absent in mammals, therapies that block microbial QS reduce the risks of host toxicity. Chen et al. developed pH-sensitive curcumin-loaded nanoparticles (Cur-DA NPs and anti-CD54@Cur-DA NPs) to inhibit QS for treating biofilm-associated bacterial infections. These NPs enhance penetration and curcumin release in acidic biofilm environments, effectively inhibiting QS and improving antibiotic efficacy. The targeting modification with anti-CD54 boosts NPs accumulation at infection sites, significantly reducing bacterial load and inflammation in vivo, suggesting a promising antimicrobial strategy (Fig. 24).

84In addition, nanomaterials have been used as delivery of antimicrobial agents, such as antibiotics and antimicrobial peptides. Immobilisation of nanomaterials on implantable devices, wound dressings, bone cement, or dental materials can serve as antibacterial coating.

85Viral infections represent a significant health challenge, posing risks to individuals worldwide. Nanomaterials have shown great advantages in the study of antiviral therapy. In general, antiviral nanomaterials can prevent viral infections by directly targeting virus particles, interfering with virus-host cell interaction, and suppressing viral proliferation. For example, the sharp edged structure of GO can cause physical damage to viral structures; Carbon dots synthesised from glycyrrhizic acid (Gly-CDs) are reported to directly inactivate porcine reproductive and respiratory syndrome virus (PRRSV), inhibit viral invasion and replication, and activate innate immunity; Ag NPs were shown to inhibit the interaction between spikes over the viral membrane and target cell membrane receptors, thereby inhibiting human immunodeficiency virus (HIV-1) attachment; Au NPs were reported to inhibit replication of foot-and-mouth disease virus (FMDV); MIP NPs that use whole viral particles as templates are able to specifically capture and rapidly remove viral particles from the environment, thereby preventing viral infections.

86In addition, nanomaterials can be used as drug carriers to deliver antiviral drugs. For example, PLGA NPs, cationic nanogels, and chitosan nanospheres can deliver bictegravir, azidothymidine, and acyclovir, respectively, resulting in benefits such as sustained release, reduced cytotoxicity and dosing, increased site-specific delivery, and improved stability and solubility.

87Nanomaterials offer promising solutions for both antibacterial and antiviral therapies through unique mechanisms and targeted delivery systems. Their ability to prevent resistance evolution, enhance drug efficacy, and reduce toxicity highlights their potential to revolutionise infectious disease treatment in healthcare applications.

88Building on the previous discussion of nanotechnology's major applications in healthcare-medical diagnostics, tissue engineering, drug delivery, gene delivery, cancer therapy, and antimicrobial/antiviral applications-this section explores the future trends of nanotechnology in the field. As nanotechnology continues to revolutionise healthcare, it offers innovative solutions that promise to enhance the efficacy and personalisation of medical treatments. Key emerging trends such as personalised medicine, theranostics, and smart drug delivery systems are particularly noteworthy. These advancements not only represent cutting-edge technological progress but also have the potential to significantly impact the future of healthcare by enabling more precise, effective, and tailored medical interventions.

89Personalised medicine aims to tailor treatments to the individual characteristics of each patient, making therapies more effective and reducing side effects. Nanotechnology plays a crucial role in this domain by enabling the development of nanoformulations that are specifically designed to interact with individual genetic profiles, thereby enhancing therapeutic outcomes. Jhawat et al. highlighted the integration of pharmacogenomics with nanotechnology, proposing that nanoformulations could lead to error-free and targeted therapeutic agent delivery, which is essential for personalised healthcare. In addition, nanoinformatics, which combines nanotechnology with artificial intelligence, is becoming a powerful tool in personalised medicine. By analysing patient-specific data, nanoinformatics enables the design of better nanomaterials for personalised drug delivery, thus improving treatment precision.

90Theranostics is an innovative approach in medicine that integrates therapeutic and diagnostic capabilities into a single platform, allowing for the simultaneous diagnosis, treatment, and monitoring of diseases. This dual functionality enhances the precision of medical interventions by utilising advanced nanomaterials and imaging techniques to deliver therapeutic agents directly to targeted sites while continuously monitoring treatment efficacy and disease progression. The real-time feedback loop provided by theranostics enables clinicians to adjust treatment strategies based on individual patient responses, optimizing therapeutic outcomes. A notable advancement in this field is optical imaging-guided nanotheranostics, which utilises advanced imaging modalities such as MRI and CT to enhance the precision of cancer treatments. This approach not only allows for accurate visualisation of tumours but also improves the monitoring of therapeutic responses and enables real-time adjustments to treatment, thereby supporting personalised medicine (Fig. 25).

91Theranostics is particularly promising in cancer care, where real-time monitoring ensures precise drug delivery to tumour sites, minimising damage to healthy tissues and reducing systemic toxicity. Furthermore, it facilitates tracking therapeutic efficacy at the molecular level, offering insights into the biological responses of tumours, which aids in early detection of resistance and supports adaptive, personalised treatment plans tailored to the cancer's evolving nature. These personalised strategies have been shown to significantly enhance patient outcomes by enabling more targeted and effective therapies. Beyond oncology, the principles of targeted delivery and real-time monitoring that define theranostics have the potential to transform the management of other conditions, including cardiovascular diseases, neurological disorders, and infectious diseases, leading to more precise, personalised, and efficient healthcare across various medical fields.

92Smart drug delivery systems are designed to release therapeutic agents in a controlled manner, specifically targeting diseased cells while minimising side effects on healthy tissues. This precision is achieved through the use of stimuli-responsive nanomaterials that can react to environmental changes such as pH, temperature, or magnetic fields. For example, polymeric nanodroplets have emerged as versatile carriers for gas and drug delivery, showing great potential in treating conditions like hypoxia and cancer. Some cutting-edge examples have been presented in the Sect. “Drug delivery” and “Gene delivery”. The integration of 3D printing with nanotechnology is also advancing smart drug delivery systems, allowing for the creation of complex, multifunctional medical products tailored to individual patient needs. This combination is expected to lead to significant advancements in personalised medicine, particularly in tissue engineering and regenerative medicine.

93Nanorobots are at the forefront of nanotechnology's impact on healthcare. These tiny robots can navigate through the body, delivering drugs precisely where they are needed, and are expected to play a significant role in personalised and precision medicine (Fig. 26). However, there are still challenges to overcome, particularly regarding safety and the scalability of production for clinical use. Another exciting development is the use of molecularly imprinted polymers in drug delivery. As discussed in Sect. “Drug delivery”, MIPs are synthetic polymers with the ability to recognise and bind specific molecules, making them ideal for targeted drug delivery systems that require high specificity and efficiency.

94Nanotechnology is set to transform healthcare by enabling more personalised, precise, and effective treatments. The continued development of personalised medicine, theranostics, and smart drug delivery systems promises to significantly enhance patient outcomes, particularly in the treatment of complex diseases like cancer. As these technologies evolve, their integration with other emerging fields, such as artificial intelligence and 3D printing, will likely lead to even more groundbreaking innovations in healthcare.

95To fully harness the advancements described in the above sections, however, it is essential to translate these technologies from the laboratory to clinical practice. This process involves conducting rigorous clinical trials, developing scalable manufacturing processes, and obtaining regulatory approval. The following section will examine the progress in transitioning nanotechnology-based innovations to clinical settings, with a particular focus on global regulatory approvals for healthcare products.

96Healthcare products are categorised into medicines (drugs) and medical devices, aligning with the regulatory frameworks of various countries. Therefore, nanotechnology and nanomaterials used in healthcare are necessarily regulated either as nanomedicines or as nanotechnology-based medical devices (NMDs) during clinical translation and commercialisation. Nanomedicines refer to medical applications that use nanomaterials to diagnose, treat, and prevent diseases. This category includes nanopharmaceuticals (i.e., drug formulations that enhance drug delivery and efficacy), nanoimaging agents (which improve the visualisation of biological processes for better diagnostics), and theranostics (which combine therapeutic and diagnostic functions into a single platform, thus allowing for simultaneous treatment and monitoring). NMDs, on the other hand, encompass a variety of medical tools and equipment that incorporate nanoscale properties to improve their functionality and compatibility with biological systems. These devices include: (i) diagnostic devices, which provide highly sensitive and specific disease detection; (ii) implantable devices, which integrate seamlessly with biological tissues; (iii) skin dressings, which offer superior wound healing properties; and (iv) surgical tools, which enhance precision and reduce invasiveness.

97Before nanomedicines and NMDs can be applied clinically, they must undergo a rigorous approval process. This process involves preclinical studies and clinical trials to ensure their safety, efficacy, and quality. Regulatory bodies such as FDA, the European Medicines Agency (EMA), and China's National Medical Products Administration (NMPA) govern this process, requiring extensive testing and evaluation to meet stringent standards.

98The current landscape of clinical research on nanomedicines and NMDs can be evaluated using data from the ClinicalTrials.gov database. Managed by the National Library of Medicine (NLM), a division of the United States National Institutes of Health (NIH), ClinicalTrials.gov is one of the largest global registries, offering extensive information on clinical trials conducted worldwide. As of August 2024, a search of this database using "nano" as a keyword in the intervention/treatment field identified 336 relevant clinical trials. Of these, 154 trials have been completed, while 20 have been suspended, withdrawn, or terminated. The conditions targeted in these 336 nano-related trials span a broad spectrum of health issues, diseases, and disorders, as illustrated in Fig. 27. This diversity of research areas highlights the extensive exploration of nanotechnology applications across various medical fields, with a notable concentration of studies focusing on dental, orthopedic, and cancer treatments.

99Despite the challenges associated with transitioning from research and development (R&D) to market—such as high costs, complex manufacturing processes, and regulatory hurdles—several nanomedicines and NMDs have successfully reached the market. These products are revolutionising healthcare by leveraging the unique properties of nanomaterials, such as improved drug bioavailability, targeting capabilities, and enhanced imaging capabilities. The emerging markets for nanomedicines and NMDs are experiencing rapid growth, driven by the increasing demand for advanced therapeutic and diagnostic solutions.

100According to a report by Precedence Research, the global nanomedicine market was valued at approximately $170 billion in 2022 and is expected to reach around $494 billion by 2032 (Fig. 28), growing at a compound annual growth rate (CAGR) of 11.3% from 2023 to 2032. The rapidly expanding domain now includes over 200 enterprises across the globe, such as Sanofi SA, Pfizer Inc., Taiwan Liposome Company Ltd, Johnson & Johnson, and Bristol-Myers Squibb Company, all of which provide a wide variety of healthcare solutions based on nanotechnology. Considerable financial resources are being allocated annually towards the advancement of nanotechnology R&D, with the total investment in the United States alone reaching approximately $40 billion over the past 20 years.

101The drug delivery segment held the largest portion of the healthcare nanotechnology (nanomedicine) market in 2022, accounting for 34% of its total, driven by the increasing prevalence of chronic and infectious diseases such as cancer and COVID-19, along with a heightened public understanding of the potential benefits of nanomedicine. Liposomes (spherical vesicles made of phospholipids with the capability to deliver both hydrophilic and hydrophobic drugs) pioneered the successful transition of nanomedicine from concept to commercial reality. Since receiving approval from the FDA in 1995, lipid-based nanomedicines have been on the market for nearly three decades. Out of all the nanomedicines currently available in the market or undergoing different stages of clinical translation, liposomes or lipid-based NPs represent the most common category, adding up to 33% of the total. Beside them, polymer-based nanomedicines, nanocrystals, inorganic-based NPs, carbon-based NPs and protein-based NPs have also gained approval and entered commercialisation, as shown in Table 1.

102In addition to nanomedicines, NMDs are being approved for marketing worldwide. The first FDA 510(k) clearance for a medical device containing nanomaterials was given in 1980. A 510(k) is a premarket submission made to the FDA to demonstrate that the device to be marketed is as safe and effective (i.e., substantially equivalent) as a legally marketed device. As of June 2024, 151 FDA 510(k)-cleared products featured the term “nano” in either the manufacturer or product name. However, not all of these products are NMDs. Table 2 lists those with published evidence confirming the use of nanomaterials or nanotechnology, including bone fillers (nano-structured hydroxyapatite), and dental resins (dimer acid derived nanohybrid composite). It also covers devices featuring nano-coatings or nano-structured surfaces, like dental implants (calcium phosphate coating), intervertebral fusion devices (hierarchical nano/microtextured surface), knee prostheses (hydroxyapatite nanocoating), vessel sealing devices (non-stick coating), trauma screws (surface with antimicrobial nanotopography).

103Some devices gain FDA approval via a different regulatory pathway, the premarket approval (PMA) process. The PMA process requires clinical trials to demonstrate the safety and efficacy of a device and is the most stringent type of device marketing application required by the FDA. As of June 2024, five manufacturers had their 75 products, each bearing “nano” in the name and including different sizes or models of the identical device, approved via the PMA process. Among these products, only the COBRA PzF NanoCoated Coronary Stent demonstrated clear evidence of using nanotechnology (Table 3). This particular product features a cobalt-chromium strut enveloped in a poly [bis(trifluoroethoxy)phosphazene] (Polyzene-F® polymer) coating with a thickness of approximately 50 nm, which has thrombo-resistant, anti-inflammatory and rapid healing effects. Exploring the 510(k) and PMA databases reveals that FDA-approved NMDs are predominantly used in orthopedic and dental applications.

104NMDs approved by NMPA show a distinct emphasis in their applications compared to those cleared by FDA, which might be attributed to the variances in healthcare market demands, industrial chains, intellectual property rights, and regulatory frameworks between China and the United States. By June 2024, NMPA-approved NMDs from Chinese manufacturers are predominantly aimed at diagnostic purposes (Table 4), featuring in vitro diagnostic kits with elements like CNTs, gold nanocages, nano-enzymes, rare-earth nanospheres, and magnetic nanobeads for identifying conditions such as myocardial infarction, renal disease, cancer, blood clots, and COVID-19. The approval list of domestic products also comprises medical dressings containing Ag NPs or nano-ceramic materials, and bone fillers made with nano-structured hydroxyapatite. For the smaller number of overseas products approved (Table 5), diagnostic devices also represent the largest category. Furthermore, several of these products, including Adaptix™ Interbody System with Titan nanoLOCK™ Surface Technology, Nano-coated LigaSure™ Maryland Jaw Thoracic Sealer/Divider, and Nano-technology Universal Dental Adhesive, had already been approved by FDA.

105In the European Union (EU), over 70 EU-certified private notified bodies regulate medical device approvals, issuing Conformité Européenne (CE) marks for EU-wide marketing. Differently from the United States and China, national authorities oversee post-market safety. As of June 2024, the European Database on Medical Devices (EUDAMED) lists 130 approved medical devices that either contain nanomaterials or have "nano" in their name. The products among them that can be identified as NMDs through publicly available information are listed in Table 6. They are mainly intended for use in the following areas: dental restorative materials, cosmetic injections, laboratory instruments, magnetic NPs for anti-cancer purposes, protein assays, COVID-19 rapid diagnostic kits, and others. Within this assortment, products related to dentistry represent the largest category, constituting over 30% of the total. This category specifically includes light-cure nanocomposites and zirconia-silica nanocomposite fillers for dental restoration. In addition, one particular example is aimed at cancer therapy: NanoTherm® AS1 is a water-based solution filled with superparamagnetic NPs, primarily made of Fe3O4 with a diameter of roughly 12 nm. These NPs function as energy transducers for magnetothermal therapy aimed at cancer treatment. To ensure the stability of these NPs within tumour tissues, their surface is coated with an aminosilane. In Europe, this formulation is applied in a dual treatment approach, combining magnetic hyperthermia therapy with radiation therapy, for patients suffering from recurrent glioblastoma multiforme (GBM). Another example, Proteonano™, represents instead a proteomics analysis technology that use magnetic NPs modified with peptides and small molecules for the identification of various protein biomarkers.

106From Tables 1–6, it is evident that while the classification of NMDs varies across regions, all systems fundamentally rely on the risk level associated with the device to determine regulatory requirements. The United States, Europe, and China all use a tiered approach, classifying devices into different categories to align regulatory requirements with the device’s potential risk, as shown in Table 7. FDA and NMPA both categorise devices into three classes: Class I for low-risk devices that require minimal oversight, Class II for moderate-risk devices needing more regulatory controls (such as 510(k) premarket notification for FDA and enhanced supervision for NMPA), and Class III for high-risk devices that support or sustain life, requiring stringent evaluation and approval processes. The EU employs a more detailed four-class system, with Class I for low-risk, Class IIa and IIb for moderate to higher-risk depending on usage duration and invasiveness, and Class III for high-risk devices. This system emphasises device invasiveness and duration of use more than the FDA or NMPA. Despite these differences, all systems aim to ensure device safety and effectiveness by increasing regulatory requirements as the risk level rises, particularly for devices that are life-supporting or implanted. These frameworks reflect a global commitment to maintaining high standards in medical device safety, adapted to each region's regulatory environment.

107The commercialisation decision for NMDs is heavily influenced by these regulatory classifications, as they dictate the level of evidence required for approval and market access. For example, devices intended for high-risk applications, such as implantable devices or those involving critical nanomaterial interactions with the human body, typically face stricter regulatory scrutiny and require more extensive clinical data. Understanding these regulatory frameworks is crucial for developers to strategise their product development and market entry effectively.

108In addition, the divergent application focuses of nanotechnology in medical devices across the United States, Europe, and China reflect differences in the clinical translation and commercialisation of nanotechnology globally, which can be attributed to several factors, including differing healthcare priorities, regulatory environments, R&D capacities, and market demands in these regions. Different regions may prioritise healthcare needs based on prevalent diseases, demographic profiles, and public health challenges. For instance, the higher emphasis on orthopedics and spinal surgery in the United States could reflect a larger aging population suffering from musculoskeletal disorders. The focus of Europe on dentistry might be due to a combination of high dental care standards and public health policies prioritising oral health. In contrast, the high interest of China for diagnostics could stem from a strategic push to improve early disease detection and management in a populous country, aiming to reduce long-term healthcare costs. In addition, the regulatory frameworks governing medical devices, including those using nanotechnology, vary significantly across regions, which can influence the type of products that reach the market. Stricter or more lenient regulations in one area of healthcare over another can steer the R&D focus. Manufacturers with superior R&D capabilities can secure a larger market share by leveraging intellectual property protection, which limits similar technological advancements of their competitors, thus fostering differentiated competition. Market demands, driven by patient needs, insurance coverage, and societal values, also influence the focus of nanotechnology applications in medical devices. The economic incentives to address specific healthcare challenges can drive companies to innovate in areas with the highest return on investment.

109The development and market introduction of nanomedicines and NMDs are ongoing, but the products available are still few compared to the extensive research indicated by 50,424 articles on 'nanomedicine' and 15,220 on 'nano medical device' found on PubMed (as of June 2024). This disparity underscores the significant hurdles in their clinical translation and commercialisation.

110The commercialisation of nanomedicines and NMDs faces several significant challenges, particularly in terms of market entry barriers and cost-effectiveness. This section explores these obstacles in detail, focusing on the financial, manufacturing, and quality control issues that impact the successful introduction of nanotechnology in healthcare.

111One of the main challenges for bringing nanomedicines and NMDs to market is meeting the stringent regulatory requirements, which are crucial to ensuring the safety, efficacy, and quality of these products. Regulatory approval typically involves comprehensive preclinical and clinical evaluations, with toxicity testing and safety assessments being essential components. Due to the unique size and surface characteristics of nanomaterials, they may exhibit toxicity profiles that differ from those of traditional materials, necessitating specific tests for acute, subacute, and chronic toxicity, as well as genotoxicity, immunotoxicity, and environmental toxicity to assess their potential impact on biological systems and the environment. Sect. “Nanotoxicity and safety risks” will provide a more in-depth discussion on the health risks of nanomaterials in vivo and in the environment, as well as the mechanisms of toxicity. Additionally, safety evaluations generally include a range of in vitro and in vivo studies to understand the biocompatibility of nanomedicines and NMDs, as well as their absorption, distribution, metabolism, and excretion (ADME) properties in the body. These studies must strictly adhere to Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP) to ensure the reliability of the tests and the consistency of the products. Figure 29 illustrates the steps necessary to bring nanomaterials to healthcare market. While these rigorous requirements help reduce uncertainties in the approval process, they also significantly increase the cost and time required for research and development, posing a major challenge to market entry. By meeting these complex regulatory requirements, nanomedicines and NMDs can successfully enter the market and provide safe and effective treatment options for patients.

112Moreover, the requirements for these evaluations can vary significantly across different regions, creating additional obstacles for companies seeking to bring their products to the global market. Regulatory agencies in various countries have different standards and procedures for the approval of nanomedicines and NMDs. For example, as described in Table 7, different regions have distinct requirements for the classification of medical devices. These discrepancies mean that companies may need to conduct additional tests and modifications to meet the specific requirements of each market, thereby increasing both time and cost. This complexity necessitates that companies carefully consider the regulatory requirements and market characteristics of each region when developing global commercialisation strategies. Sect. “Current regulatory policies around the globe” will provide a detailed discussion on the current state of global regulations and offer recommendations for improvement, helping companies better navigate these challenges and achieve global market entry for nanomedicines and NMDs.

113Developing nanomedicines is an expensive and resource-intensive process that poses significant financial challenges for companies, particularly for smaller firms and start-ups. The costs associated with R&D encompass a wide range of activities, including the design, synthesis, characterisation, and testing of nanomaterials. Each of these stages requires specialised equipment and expertise, which can drive up expenses. Additionally, scaling up production from laboratory-scale synthesis to manufacturing quantities suitable for clinical trials and eventual market supply involves substantial investment in infrastructure and technology.

114Beyond the initial development costs, conducting extensive clinical trials to meet regulatory standards is another major financial hurdle. Clinical trials, which are necessary to establish the safety, efficacy, and quality of nanomedicines, often involve multiple phases and require significant resources to manage and execute. These trials are not only costly due to the need for specialised staff, facilities, and materials but also time-consuming, which further delays the potential return on investment. Smaller companies and start-ups may find these expenses particularly prohibitive, as they typically lack the financial reserves and access to capital that larger pharmaceutical firms possess.

115The financial burden of developing nanomedicines is further compounded by the uncertainty of return on investment. The innovative nature of nanomedicines means that there is often limited prior data to support their efficacy and safety, leading to a higher risk of delays or failures in the approval process. This uncertainty can deter investors and make it difficult for companies to secure the necessary funding to carry their products through to market.

116Given these substantial financial barriers, it is crucial for companies to carefully strategise their R&D investments and seek collaborative partnerships or alternative funding sources to mitigate risks and enhance their chances of successful market entry.

117Scaling up the production of nanomedicines from laboratory research to commercial-scale manufacturing presents unique challenges due to the distinct properties of nanomaterials, such as their small size, high surface area, and reactivity. These characteristics necessitate specialised manufacturing processes and equipment to maintain consistent quality. Even slight variations in particle size or surface properties can significantly impact the efficacy and safety of the final product.

118Ensuring reproducibility across large-scale production is difficult, as processes optimised at a small scale may not perform identically when scaled up, potentially leading to variability. This requires strict control over production conditions and process parameters to ensure uniformity. Adherence to GMP guidelines is essential to meet regulatory standards, involving rigorous quality control measures, real-time monitoring, and validation of processes to detect and correct deviations.

119Additionally, manufacturing nanomedicines requires advanced analytical techniques to accurately characterise nanomaterials, such as dynamic light scattering and electron microscopy, to ensure consistent particle size, morphology, and surface chemistry. These requirements increase the complexity and cost of production but are crucial for ensuring product quality and safety.

120The integration of nanotechnology into healthcare brings forth several ethical considerations that must be addressed to ensure responsible and equitable use. One of the primary concerns is the issue of informed consent. Nanomedicines and NMDs often involve complex mechanisms and potential risks that may not be fully understood by patients. The novelty and intricacies of these technologies can make it challenging for patients to comprehend the full scope of benefits, risks, and long-term implications associated with their use. This can lead to difficulties in achieving truly informed consent, as patients may not have all the necessary information to make well-informed decisions about their treatments. Therefore, healthcare providers have a duty to develop comprehensive educational materials and employ effective communication strategies that clearly explain the nature and implications of nanotechnology-based interventions in a way that is understandable to patients, thus safeguarding patient autonomy.

121In addition to informed consent, ethical considerations also extend to issues of privacy and equitable access. Nano-enabled diagnostics and treatments could collect extensive biological and genetic data, raising concerns about data security, privacy breaches, and the potential misuse of sensitive information. This data, if inadequately protected, could be exploited by third parties such as insurance companies or employers, leading to discrimination or stigmatisation based on genetic predispositions. Furthermore, the high cost of developing and manufacturing nanotechnology-based healthcare products can create barriers to access, particularly for disadvantaged populations or those in low-income countries. The unequal distribution of these advanced technologies risks widening existing healthcare disparities. To address these ethical challenges, it is crucial to implement robust data protection regulations and develop policies that promote equitable access to nanotechnology-based innovations, ensuring that all patients, regardless of their socioeconomic status, can benefit from these advancements in healthcare.

122The cost-effectiveness of nanomedicines and NMDs is a critical consideration in their development and market adoption. Although these technologies offer significant clinical advantages, such as improved therapeutic outcomes, targeted delivery, and enhanced diagnostic capabilities, they also involve substantial costs. The high initial investments required for the specialised synthesis of nanomaterials and the advanced technologies needed for their production contribute to increased development expenses compared to traditional pharmaceuticals and medical devices. Additionally, both nanomedicines and NMDs require extensive preclinical and clinical testing to meet stringent regulatory standards, further adding to the financial burden. However, these high costs can be offset by the potential long-term benefits, such as enhanced drug delivery, reduced side effects, fewer invasive procedures, and shorter recovery times, which can ultimately lead to lower overall healthcare costs. Moreover, implementing policies that promote equitable access and affordability, as mentioned previously, can enhance the cost-effectiveness of these technologies by ensuring that a wider patient population benefits from their advantages. Comprehensive economic evaluations that account for both direct and indirect costs are essential to determine the value these technologies bring to healthcare systems. By balancing these costs against the potential benefits, nanomedicines and NMDs can be seen as viable options that not only improve patient outcomes but also contribute to economic sustainability in healthcare.

123The significant potential benefits of using nanotechnology in healthcare are undoubtedly appealing. However, the issue of biocompatibility must be addressed when any foreign substance is introduced into the human body for medical reasons, along with the environmental effects associated with commercialisation and market entry. Conducting a comprehensive and reliable evaluation of their toxicity throughout their lifecycle poses a challenge for professionals and organisations alike. This is because the reduction in size or dimensions, particularly to nanoscale in one or two dimensions, can lead to not only novel properties but also potentially unconventional toxicity behaviour.

124Research has demonstrated that certain medical conditions may result from the improper exposure to nanomaterials. Mesothelioma, a type of cancer that forms in the protective lining of various internal organs, serves as a notable example, often linked to asbestos exposure. Asbestos, a collection of minerals composed of tiny, fibrous particles, was extensively used in the construction industry in the 1970s and shares similarities in size with nanomaterials. These tiny asbestos fibres can be inhaled and embedded in the lung tissue, causing damage over prolonged periods (Fig. 30).

125Although over 60 countries worldwide have enacted bans on asbestos, there remains a valid concern that other substances with similar sizes and shapes, such as nanofibers, could pose similar health risks if they are introduced into the human body in a comparable manner. NPs have been shown to be inhaled and deposited by diffusion in the small-diameter tubes of the lower part of the respiratory tract and in the alveoli. Furthermore, epidemiological research indicates that exposure to NPs is linked to an increased risk of cardiovascular and respiratory diseases. Regrettably, advancements in research on this subject have been limited; more specifically, there has not been a consensus on a standardised methodology for toxicological testing and analysis among medical professionals and toxicologists. This challenge arises partly due to the need for a multidisciplinary approach that encompasses materials science, chemistry, physics, toxicology, and environmental science.

126While human health risk assessment focuses on determining the acceptability of health risks from medical products to humans under specific exposure scenarios, the life cycle assessment of medical products evaluates and compares the environmental impacts of the products or processes throughout their life cycle, encompassing their potential (negative) impacts on human health among other effects. Currently, data on the impact of nanomaterials on aquatic life and plants are limited, with a shortage of suitable research methods. Despite variations in their objectives, processes, and scope, both types of risk assessments depend on similar data for insights into nanomaterial toxicity. There is a consensus on the importance of assessing the ecological and environmental safety of nanomaterials, which necessitates the development of suitable models and new methods. The following sections contain a discussion on the safety risks of nanomaterials from both health and environmental perspectives.

127Typically, the body manages foreign chemicals through processes including exposure, absorption, distribution, metabolism, and excretion. These processes can be analysed through toxico-kinetics and a risk-based approach. Using logical and scientific rationale, along with ISO 10993, should elucidate the in vivo biosafety risk of a medical product. Yet, small particles are more easily taken up by cells, cross epithelial and endothelial membranes, undergo transcytosis, enter the blood and lymphatic circulatory systems, and ultimately accumulate in sensitive organs like the bone marrow, lymph nodes, spleen, and heart, therefore exhibiting significantly different dose sensitivities and kinetics. Table 8 provides a comprehensive list of the primary and secondary biological barriers that NPs can penetrate, along with the organs they may accumulate in, offering an initial overview of the potential fate of NPs upon exposure to humans through different pathways.

128Specifically for the respiratory system, a predictive model has been developed to detail the behaviour of NPs within it. The model suggests that smaller particles are more prone to settle in the respiratory tract, with their distribution across various regions being size-dependent. NPs measuring 5 nm are equally likely to settle in the nasopharyngeal (upper airways), tracheobronchial, and alveolar areas. However, for particles smaller than 5 nm, there is a higher tendency for them to settle in the nasopharyngeal area, while those larger than 5 nm predominantly settle in the alveolar region. This variance in settlement locations is likely to affect the biological interactions of the NPs. This model, however, exhibits limitations in two main areas: firstly, it was designed specifically for spherical NPs, leaving uncertainty about its applicability to NPs of different shapes; secondly, it uses default material behaviours primarily derived from studies on thorium, uranium, or technetium, despite the fact that the behaviour of a nanoparticle is highly influenced by its chemical composition and surface properties. To add even more complexity to an already difficult challenge, the final destinations of NPs are diverse. To provide an example, after administering 20 nm colloidal Au NPs to mice through intratracheal instillation, these particles were found not only at the basal membrane between alveolar and endothelial cells but also on the surface of blood vessel endothelial cells, with a small fraction even detected in the bloodstream. Extensive research has confirmed that NPs can cross biological barriers, impacting the parenchymal components of organs either toxically or therapeutically, as detailed in prior reviews.

129These findings lead to two key agreements: firstly, the toxicity of metallic NPs cannot be inferred from the existing toxicology of their bulk metal counterparts, and secondly, once inside an organism, NPs can distribute across tissues in ways not governed by known physiological processes. Consequently, there is no clear guidance for nano-toxicology evaluation using traditional toxicological approaches, primarily due to the intricate interactions between nanomedicines and biological systems. To advance in this area, it is crucial to understand the mechanisms behind the complex reactions to nanomaterial exposure. This section outlines common mechanisms of action, as listed in Table 9.

130When nanomaterials enter a biological system, they inevitably engage with a variety of biological components, such as DNA, proteins, membranes, cells, and organelles, based on the specific context. The surfaces of these nanomaterials are quickly coated by biomolecules from the biological environment, with proteins being the most significant, forming what is known as a “protein corona.” This corona bestows a biological identity on the nanomaterials, influencing their subsequent interactions within the biological environment. Notably, the makeup of the “protein corona” is subject to change, determined by the concentrations and affinities of its different protein constituents to the nanomaterial surface. Simultaneously, a key characteristic of nanomaterials is their relatively high surface-area-to-mass ratio, enabling them to adsorb significant quantities of materials per unit of mass. This capacity to bind a wide array of substances is thought to significantly influence their behaviour within cells under certain conditions. For instance, an in vitro investigation of polystyrene NPs demonstrated that NPs with a positive charge could penetrate cells 20 to 40 times more rapidly than those with a negative charge. For NPs administered intravenously, their distribution across different organs is ultimately influenced by the plasma proteins that adhere to their surfaces. The distinct physical and chemical characteristics of these NPs—such as their size, surface area, modifications, charge, hydrophobic/hydrophilic properties, and redox activity—along with the in vivo microenvironment, dictate their varying patterns of interaction with proteins and lipids across various organ tissues and cells. This interaction determines the eventual location and destiny of the NPs within the body.

131Research on inhaled nanomaterials has shown that while cells can engulf particles of most sizes, those smaller than 100 nm can move across alveolar epithelial cells via diffusion through the cell membrane lipid bilayer or, in certain cases, cross the air-blood barrier through gaps between cells. Experiments involving Au NPs and Ag NPs, coated with antibodies and of various sizes, demonstrated their role in the process of membrane receptor internalisation. The binding and activation of these membrane receptors, along with the resulting protein expression, were notably influenced by the size of the NPs. NPs within the 2 to 100 nm range influenced signal pathways critical for cell function, with those measuring 7, 40, and 50 nm showing the most pronounced effects (Fig. 31). A summary of size-dependent cellular uptake of nanomaterials in regarding to the examined cell lines and major conclusions is presented in Table 10.

132By interfering with specific transmembrane proteins, NPs can regulate internalisation and other fundamental cell functions, and also penetrate biological barriers. This is achieved by inducing the degradation, conformational change, and disintegration of proteins that link adjacent cells, facilitating paracellular transport. There are various types of intercellular junctions, including tight junctions (TJs), adherent junctions (AJs), desmosomes, and gap junctions (GJs). Although they serve different functions, desmosomes provide strong linkages that maintain stable adhesion between cells exposed to mechanical stress, such as those in the bladder and myocardium; GJs are primarily used as channels for the exchange of ions and signal molecules between neighbouring cells, playing a crucial role in intercellular communication. Regarding the function of paracellular permeability, which is an essential component in sealing the paracellular route in epithelial and certain endothelial barriers (e.g., blood–brain barrier), the structure of TJs is deemed responsible. They “glue” together portions of neighbouring cell membranes adjacent to the apical side, preventing lipids and specific proteins from mixing between the apical and basal sides of the cell, and limiting the space between cells to a very narrow range (from about 5 Å to 50 Å in different tissues).

133A detailed study investigated the impact of Au NPs size on their interactions with the paracellular AJs (Fig. 32).

134It was found that Au NPs with diameters of 18 nm and 30 nm were sufficiently small to migrate into the AJs and disrupt vascular endothelial (VE)-cadherin homophilic interactions, whereas Au NPs measuring 70 nm in diameter could not cause significant disruption. Another study investigated the impact of pristine graphene on brain microvascular endothelial cells (BMVECs), revealing a reduction in the expression of the TJ protein occludin, increased permeability, and a resulting increase in BMVEC cell death. Additionally, a significant drop in mitochondrial membrane potential was observed in rats exposed to Ag NPs, leading to a decrease in adenosine triphosphate (ATP) levels and setting the stage for the onset of cell autophagy. The study also revealed that autophagy is triggered in the brains of rats exposed to low doses of Ag NPs, unlike those exposed to silver citrate, highlighting how differences in surface chemistry can lead to distinct toxicity profiles.

135The interaction between nanomaterials and proteins in the human body is particularly complex, especially since nanomaterials covered with proteins that trigger macrophage phagocytosis are identified by immune system cells with specific receptors. These interactions are not fixed and vary with the changing protein environment within the body, where abundant proteins may be gradually replaced by less abundant ones that have a higher affinity for the nanomaterials, indicating a dynamic process. The increasingly understood mechanism of interaction between nanomaterials and proteins at the molecular level has been illustrated in a recent publication.

136Surface chemistry may result in varied nanotoxicity behaviour via diverse biochemical interactions. However, as the physical attributes of nanomaterials, such as shape and size, are scaled down, their significance becomes increasingly non-negligible in comparison to surface chemistry.

137A study by Yuan et al. examined how diameter influences the uptake of NPs with a consistent surface ligand density through mathematical modeling. The authors identified the most effective diameters for endocytosis as being approximately 30–50 nm. However, as each cell type has its distinct phenotype, the most effective size and distribution for NPs uptake should be determined individually, based on the specific cell type under examination and the surface chemistry involved. In another study published by Akcan et al., a series of toxicity behaviours of Au NPs were detailed: 50 nm particles showed maximum uptake by HeLa cells; particles ranging from 45 to 50 nm activated membrane receptors in SK-BR-3 cells; those between 15 and 50 nm had the capacity to cross the blood–brain barrier in mice; and 15 nm particles displayed the most extensive distribution across various organs (in mice), including blood, liver, lungs, spleen, kidneys, brain, heart, and stomach. Inside the cell, size remains significant. Williams et al. reported that the entry of cadmium telluride quantum dots (CdTe QDs) into various subcellular organelles varies by size and cell type: QDs smaller than 2.1 nm penetrate the nucleus, while those measuring 4.4 nm localise within the cytoplasm.

138Beyond the common size parameter for describing uniform nanomaterials (typically NPs), an important study published by Li et al. has showed that ultrathin 2D synthetic materials like graphene, ranging from 0.5 to 10 μm in lateral size, could be fully internalised by cells after initially attaching by their edges (Fig. 33).

139The study provided an energy barrier-based explanation, indicating that for small graphene pieces, thermal motion and entropic forces near the cell membrane initially align the piece with the membrane plane, leading to spontaneous piercing by corners with a minimal energy barrier (about KBT level). It was noted that in the absence of sharp edges, cell membranes present a significant energy barrier to the penetration by long graphene edges, even if they are only atomically thin. This highlights that local sharp features can facilitate penetration when the activation barriers are surpassed, regardless of whether the overall dimensions are in the nanometer or micrometer scale.

140As the size of NPs decreases, the proportion of surface atoms to the total number of atoms in the NPs significantly increases, enhancing the surface capacity and surface tension of the particles. This leads to alterations in the physicochemical properties of the NPs, a phenomenon known as the surface effect or interface effect. When the surface atoms are exposed, they lack surrounding atoms, possess numerous unpaired bond forces, and are more likely to react with other atoms to reach a stable state, thus exhibiting high chemical reactivity. The substantial specific surface area of NPs increases the number of surface atoms, raises the level of structural disorder, and results in mismatched bonding states, creating many active sites.

141Specifically, in the context of copper nanoparticles (Cu NPs), when these particles enter the digestive system, the acidic gastric fluid environment (with a pH of about 2) triggers the rapid conversion of ultra-reactive nano-metallic particles into their ionic form. Cu NPs transform hydrogen ions more swiftly than their micron-sized counterparts, leading to an excessive accumulation of Cu ions in the body and consequent toxicity. This toxicity escalates as the size of the Cu particles decreases, with significant toxicity observed at 17 μm for micron-sized copper particles and at 23.5 nm for Cu NPs. While inert micron-sized Cu only causes intestinal blockage at extremely high doses (5000 mg/kg), in gastric fluids, the highly reactive Cu NPs quickly convert to ionic form, rapidly relocating to the liver and kidneys for metabolic processing and elimination. The swift generation of numerous Cu ions by the NPs induces Cu ions overload in the body, resulting in liver and kidney damage and the disruption of tissue function.

142The primary internal and biological toxic effects from nanomaterials are largely due to their ability to generate an overabundance of ROS such as hydroxyl radicals, singlet oxygen, hydrogen peroxide, and superoxide anion radicals These free radical species including ROS and RNS, are highly reactive because of their unpaired electrons, leading them to interact with different cellular and subcellular structures and resulting in damage to cell membranes, lysosomes, DNA, and mitochondria, ultimately causing cell death through apoptosis and necrosis. The excessive generation of these radicals disrupts normal cellular signaling and mitogenic responses, impairing cell function

143Oxidative stress is a critical factor in primary indirect genotoxicity, primarily due to the action of free radicals. These reactive species can interact with cellular biomolecules, including DNA, leading to significant cellular damage. ROS are particularly harmful as they can oxidize purines and pyrimidines in DNA, as well as cause strand breaks. Although cells have repair mechanisms to address this damage, these processes are not always successful, potentially resulting in gene mutations or extensive chromosomal abnormalities. Moreover, nanomaterials can induce DNA damage through additional mechanisms. They may directly interact with DNA or interfere with the processes of DNA replication and cell division. Nanomaterials can also affect protein kinases, which are crucial for regulating key cell cycle events, such as DNA replication and cell division, thereby further contributing to genomic instability.

144Ag, silica, amorphous silica, Au, and ZnO nanomaterials have been identified as causing human cell toxicity by both increasing ROS production and damaging DNA. Similarly, carbon-based nanomaterials like C60 fullerene have been noted for their potential to generate free radicals. C60 and single-walled CNTs can become photoactivated, leading to intersystem crossing (ISC), which generates free electrons and subsequently results in ROS formation.

145Moreover, free radicals can trigger an inflammatory response by accumulating in alveolar macrophages and inducing significant inflammation. If not addressed, this inflammation can lead to various pulmonary conditions, including lung cancer.

146From the standpoint of drugs and medical devices, potential safety concerns typically fall into four main categories: (i) systemic toxicity, which is especially relevant for long-term exposure in the case of permanent implants, (ii) local toxicity, (iii) carcinogenicity, and (iv) special considerations, which depend on the device's application, such as blood contact or interactions with the central nervous system. The introduction of nanomaterials complicates the evaluation of each of these safety issues. Therefore, alongside fundamental research into the interactions between these novel materials and biological systems, this review provides a concise examination of the safety concerns associated with extensively studied nanotechnology materials to enhance understanding.

147Systemic toxicity of dispersive nanomaterials, whether they are manufactured or naturally occurring, is heavily influenced by their biokinetics. This is typically evaluated using the ADME(T) framework, where ‘A’ represents administration, ‘D’ denotes distribution, ‘M’ stands for metabolism, ‘E’ signifies elimination, and ‘T’ refers to toxicity. Understanding the biodistribution and clearance rates of nanomaterials is particularly complex and challenging, which has significantly impeded the broader clinical application of nanomedicines and nanotechnology-based devices.

148Joël Bourquin’s review examined the long-term biological fate of various clinically relevant nanomaterials, including liposomes, micelles, Au NPs, SPIONs, silica, and polymers. The review identified the kidneys, testes, liver, and spleen as primary target organs for dispersive nanomaterials. For Au NPs, the study found that their distribution and retention in these organs were influenced by factors beyond particle size, such as surface properties and coating materials. As shown in Table 11, Au NPs of different sizes (ranging from 2 to 110 nm) demonstrated similar patterns of organ accumulation and variable clearance times, indicating that size alone does not reliably predict their behaviour in biological systems. This data highlights that Au NPs exhibit consistent biodistribution across various sizes, with accumulation in several organs regardless of particle dimensions. Additionally, the clearance times for these NPs are not directly correlated with size, suggesting that other factors, including surface chemistry and shape, have a significant impact. The importance of these factors emphasises that a comprehensive understanding of NPs behaviour requires considering properties beyond size, such as surface characteristics and coatings, to accurately predict their biological interactions and clearance.

149High surface activity can lead to aggregation, which makes nanomaterials more easily recognised and phagocytised by macrophages, particularly in blood-rich organs such as the liver and spleen. This recognition and capture process significantly impacts the biodistribution and retention of NPs in the body. Furthermore, surface chemistry plays a vital role in NPs behaviour; certain surface characteristics may cause NPs to cluster, resulting in increased accumulation in organs like the kidneys and complicating their excretion. Additionally, variations in surface charge can affect how NPs interact with and are internalised by tissue cells, further influencing their biodistribution. These findings underscore that understanding the biological fate of NPs requires a comprehensive analysis of surface properties, as these factors are critical determinants of their interactions within biological systems and their eventual clearance from the body.

150In addition to size and surface properties, the shape of nanomaterials is a critical factor in evaluating their toxic properties. Carbon-based nanomaterials, such as graphene oxide (GO), exemplify how different shapes—such as sheets, flakes, and nanoribbons—can affect the rate and extent of internalisation and interactions with biological structures. For instance, irregularly shaped GO sheets are cleared more slowly, leading to prolonged exposure and increased toxicity, whereas spherical GO NPs are cleared more rapidly, reducing long-term toxicity.

151Ultimately, the systemic toxicity of nanotechnology-based drugs and devices depends on a comprehensive understanding of biodistribution and clearance processes. This understanding requires not only a detailed study of the size, shape, and physicochemical properties of nanomaterials but also consideration of how these materials are applied in the human body. Manufacturers must also consider the potential generation of nanoscale debris during long-term use, which could impact safety and efficacy.

152Local toxicity of nanomaterials is often associated with their route of administration, such as topical application or the site of implantation. Research has shown that Ag NPs, for example, can induce local toxicity at the point of entry, triggering an inflammatory response from the immune system. When nanomaterials interact with local tissues, they can provoke inflammation and lead to tissue damage. For instance, prolonged exposure to long asbestos fibers can result in fibrosis, characterised by the accumulation of excess fibrous connective tissue, which can impair organ function and lead to disease. This local toxicity can arise from the intrinsic properties of the materials themselves or from their interactions with biological molecules, leading to chronic inflammation. A notable example is breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), which has been identified in patients with various types of textured implants, used for both breast cancer reconstruction and cosmetic purposes. Due to the lack of specific tracking of implant textures, the risk of this disease remains inconclusive at both individual and societal levels. Furthermore, the effects of nanostructured surface topography on interactions with surrounding tissues have not been extensively studied from a nanotoxicology perspective, as highlighted in the regulatory discussions in Sect. “Current regulatory policies around the globe”.

153Patient-based investigations have confirmed that the surface roughness of silicone mammary implants significantly influences both acute and early-stage chronic fibrotic responses. The adherence of proteins to rough surfaces can mediate pro-inflammatory and profibrotic processes, suggesting that surface roughness plays a role in modulating fibrosis and enhancing the immune response. Additionally, another study demonstrated that nanostructures with a higher aspect ratio on titanium substrates can alter the elastic modulus of the material surface, thereby inducing macrophage polarisation toward the M1 phenotype and triggering intense immune responses. These findings underscore the importance of considering surface topography in the design of nanomaterials, as it plays a crucial role in interactions with proteins and subsequent local biological reactions, beyond the well-studied effects of surface chemistry.

154Furthermore, the inflammatory response is amplified by the activation of the complement system, which leads to the production of chemoattractant molecules that recruit and activate additional innate immune cells. Over the years, there has been growing recognition of the role that complement activation plays in the interaction of engineered nanomaterials, including nanomedicines, with the immune system. While it is well-established that surface properties such as chemistry, area, and energy influence protein adsorption, including that of complement proteins, the mechanisms by which the complement system is specifically activated at sites of local exposure to nanomaterials remain less understood. These gaps in understanding highlight the need for further research into how surface properties contribute to immune responses at the molecular level.

155The assessment of carcinogenicity risk for nanomaterials typically relies on theoretical analysis and existing data rather than new carcinogenicity testing, especially when the risks can be adequately evaluated or managed without additional studies. Long-term carcinogenicity studies are costly and time-consuming, often requiring two to three years to complete, which poses significant economic concerns for manufacturers. Therefore, understanding the genotoxicity of nanomaterials is crucial, as genotoxicity is a key aspect of carcinogenesis. Recent research has extensively studied the genotoxic effects of nanomaterials and the mechanisms leading to transient or permanent genetic changes. Genotoxicity is generally categorised into two main mechanisms: primary and secondary.

156Primary genotoxicity can be further divided into direct and indirect mechanisms. Direct genotoxicity occurs when nanomaterials physically interact with DNA within the nucleus, leading to DNA damage such as breaks, lesions, or chromosomal alterations. Indirect genotoxicity, on the other hand, is often associated with the generation of ROS induced by nanomaterials or the release of toxic ions from their dissolution. These ROS can cause significant DNA damage through oxidative stress mechanisms, such as the Fenton-type reaction described in Sect. “Oxidative stress and high reactivity”. To determine whether primary genotoxicity is direct or indirect, it is essential to investigate the mechanisms of nanomaterial uptake and their ability to enter the nucleus, as discussed in Sects. “Transcellular transport mechanisms” and “Paracellular transport mechanism”. For instance, smaller nanomaterials measuring only a few nanometres can penetrate the nucleus via nuclear pores. However, larger nanomaterials have also been observed within the nucleus, suggesting alternative pathways for nuclear entry, such as endocytosis.

157Secondary genotoxicity represents the predominant mechanism of nanomaterial-induced genotoxicity and is mediated by ROS produced by inflammatory cells. When nanomaterials activate phagocytes, they can initiate an oxidative burst, triggering an inflammatory response aimed at clearing foreign materials. If this clearance is unsuccessful, as is often the case with inhaled nanomaterials, it can lead to a chronic immune response and sustained genotoxic effects. This form of genotoxicity is challenging to study using standard in vitro methods and has primarily been investigated in vivo, focusing on chronic inflammation caused by immune cells such as macrophages and neutrophils. These findings underscore the importance of carefully designing the surface chemistry and size of nanomaterials to control their ROS-inducing potential, which is critical during the manufacturing development phase.

158Several studies have highlighted the variability in genotoxic effects depending on the type and coating of NPs. For example, Uygur et al. compared the toxicity of dialysed pristine Ag NPs with a size of 15 nm, PEG-coated Ag NPs (PEGylated Ag NPs), and silver nanorods across various cell lines. Their findings demonstrated that all these forms of Ag NPs were genotoxic to peripheral blood cells. Similarly, Foldbjerg et al. investigated polyvinylpyrrolidone (PVP)-coated Ag NPs, with primary sizes exceeding 50 nm, using human adenocarcinomic alveolar epithelial cells (A549). They detected bulky DNA adducts in the nucleus through 32P post-labelling, which strongly correlated with oxidative stress. Conversely, Singh et al. utilised sophorolipid, a novel glycolipid, to conjugate 10 nm Ag NPs and found no genotoxicity in human liver carcinoma cells (Hep G2) at concentrations up to 100 μg/mL. Additionally, Kim et al. reported that Ag NPs caused DNA damage in BEAS-2B cells and mouse lymphoma cells (L5178Y), although they did not exhibit mutagenicity. Recent studies have also found that starch-coated Ag NPs, with primary sizes ranging from 6 to 20 nm, were cytotoxic, genotoxic, and antiproliferative in human fibroblasts and glioblastoma cells. These findings suggest that the genotoxicity of Ag NPs is highly dependent on their size and surface coating, highlighting the importance of surface properties in determining their biological interactions and effects.

159The role of surface properties is also evident in semiconductors like metal oxides, which generate electron–hole pairs upon energy exposure (e.g., from light) a and subsequently produce ROS. The risk of oxidative stress from these materials is significantly influenced by the chemical interactions of their surfaces with the environment. Rossi et al. demonstrated that the pulmonary effects observed in mice following acute and subacute inhalation of various coated or uncoated TiO2 NPs could not be attributed to particle size or surface area alone. Instead, these effects were primarily influenced by the surface coating of the TiO2 particles. Among four types of TiO2 NPs with diameters ranging from 10 to 40 nm, only the uncoated TiO2 NPs did not induce pulmonary inflammation, likely due to differences in electron–hole recombination tendencies caused by the coatings. This electron–hole recombination effect is a well-known mechanism in the photocatalytic field.

160In summary, the genotoxicity and carcinogenicity of nanomaterials are complex phenomena influenced by multiple factors, including size, surface chemistry, and coating materials. A comprehensive understanding of these factors is essential for accurately assessing the risks associated with nanomaterials and for guiding their safe design and application in various fields.

161In risk analysis, special considerations must be tailored to specific product scenarios. For example, for products that involve blood contact, beyond conventional toxicity risks, it is crucial to consider haemocompatibility. Given the broad scope of this comprehensive review, which encompasses a wide range of product types, it is challenging to systematically analyse each specific hazard in detail. Therefore, we have chosen to highlight some recent studies on the risks associated with nanomaterials. Keeping abreast of the latest research findings is vital for risk analysis and is particularly important for R&D engineers and scientists in developing safe and effective nanomaterials.

162Jack et al. recently conducted a study on the toxicity potential of highly purified, metal-free, and endotoxin-free GO nanosheets. The study focused on two precisely defined size ranges of GO nanosheets: small (ranging from 2 μm to 50 nm) and ultrasmall (ranging from 300 to 10 nm). The findings revealed that when introduced into the human airway, these GO nanosheets formed airborne aggregates with a median size of 80–90 nm. This size distribution is significant for blood-contact products, as the study also found that both small and ultrasmall GO increased blood thrombogenicity in in vitro coagulation assays compared to air exposure. These results suggest that the thrombotic potential of GO must be carefully considered in the design of products involving blood contact.

163Similarly, a study on nano-silicon dioxide (nano-SiO2) investigated the cytotoxic effects of orally administered nano-SiO2 particles ranging in size from 20 to 30 nm at doses of 300, 600, and 900 mg/kg/day over 20 days. The results indicated varying levels of cytotoxicity, with the highest doses causing significant toxicity in the liver and lungs, and the intermediate dose primarily affecting the kidneys and lungs. These findings provide essential insights into the risk assessment for oral nanomedicine applications, highlighting the need for careful dose and toxicity evaluations based on specific organ sensitivity.

164These studies not only deepen our understanding of nanotoxicity but also underscore the complexity of assessing risks associated with nanomaterials. They highlight the importance of not assuming all risks are fully controlled and the need for thorough biological risk evaluations. For scientists and R&D engineers, regularly reviewing and analysing the latest research developments is crucial for guiding the development of safe and effective nanomaterials. By integrating the most current scientific insights into their design and evaluation processes, researchers and developers can better anticipate and mitigate potential risks associated with nanomaterial use.

165Nanotechnology has the potential to be a beneficial tool in environmental cleanup efforts by aiding in the treatment and prevention of pollution from hazardous substances, but it can also present risks to the ecosystem if not properly managed. One major concern is that the unique properties of nanomaterials, such as their small size and high reactivity, can lead to unexpected ecological consequences. Studies have shown that nanomaterials, such as Ag NPs and TiO2 NPs, can induce toxicity in aquatic and terrestrial organisms, which may disrupt local ecosystems and biodiversity.

166In the evaluation of risks from newly created engineered nanomaterials, it is widely agreed, and we share this view, that while the conventional approach to environmental risk assessment, which involves assessing both exposure and potential hazards, remains applicable to nanotechnology, it must be further adapted to consider the specific mechanisms unique to nanomaterials. Handy et al. have offered an extensive review based on regulatory guidelines, including a flowchart for assessing toxicity in water and soil environments and a summary of standard tests of the Organisation for Economic Co-operation and Development (OECD) for ecotoxicity.

167Additionally, there have been calls for caution regarding environmental considerations, suggesting that hazard assessments for nanomaterials should also encompass studies on their behavior in environmentally aged states, including non-nanomaterial entities like dissolution products. Once nanomaterials are released into natural ecosystems, they may undergo transformations that significantly affect their toxicity and environmental fate. Thus, more comprehensive research is needed on how environmental conditions, such as pH, temperature, and the presence of natural organic matter, affect the surface chemistry, aggregation state, and solubility of nanomaterials. These factors, in turn, influence their interaction with biota and ecological systems.

168Generally, risk assessment for nanomaterials should cover five stages across the lifecycle: resource acquisition, production process, utilisation stage, elimination process, and waste management. Furthermore, the risk assessment must ensure the integrity and standardisation of the evaluation across these stages, with special emphasis on the waste management stage. A critical challenge in this assessment is the development of reliable environmental monitoring techniques that can track the concentration, transformation, and bioavailability of nanomaterials in different environmental compartments (e.g., air, water, soil). A more integrated approach is suggested, combining multiple techniques such as single-particle inductively coupled plasma mass spectrometry (spICP-MS), transmission electron microscopy (TEM), and field-flow fractionation (FFF) coupled with light scattering detection to achieve real-time and precise detection of nanomaterials in complex matrices.

169Upon entering natural environments, nanomaterials may degrade into various forms under the influence of environmental processes, resulting in the final environmental aged state, which includes changes like surface transformation and dissolution. For instance, the aging process of nanomaterials in aquatic environments can result in the formation of new nanomaterial species with altered reactivity and toxicity. Therefore, risk assessments should not only focus on pristine nanomaterials but should also extend to the aged forms, as these might pose different risks. Long-term monitoring and predictive modeling of these aged forms are crucial to assess their cumulative ecological impacts.

170A research work about the lifecycle aging of Ag and TiO2 nanomaterials and its distribution of the different environmental aged states was done by Adam et al.. It was modeled that release into surface water and soil primarily occur in altered forms (with 34–58% and 78–86% in the 25th and 75th percentiles, respectively, averaging 53% and 82%), whereas air releases were mainly in unaltered or matrix-encapsulated forms (ranging 38–46% and 36–44%, with averages of 42% and 40%). The variation in the release pathways across different environmental compartments highlights the need for a more systematic study of the nanomaterial release patterns in each medium and their potential environmental and ecological impact.

171In response to the complex transformation pathways of nanomaterials, such as hetero-aggregation, dissolution, and sulphidation, it is recommended that risk assessments incorporate detailed monitoring and predictive models of these processes within natural ecosystems. Monitoring should focus on both short-term and long-term effects of nanomaterial exposure in critical environmental compartments. Furthermore, the integration of environmental data from different regions and ecosystems is essential to better understand the global distribution and impact of nanomaterials, which can support more informed regulatory frameworks.

172Once nanomaterials enter ecosystems through industrial discharges or agricultural activities, they may affect the growth and development of rare medicinal plants, crop yield, and the metabolism of primary and secondary metabolites. TiO2 NPs, commonly used in daily life, were studied for their effect on Luteolin, a sensitive anticancer flavonoid. The findings showed that the impact was directly proportional to the level of nanoparticle contamination. Flavonoids can undergo various chemical modifications when exposed to metallic oxide NPs, depending on factors such as pH, temperature, and the presence of other chemical species.

173In conclusion, the environmental risk analysis approach should be improved to fully account for the environmental aging of nanomaterials through specific transformation pathways such as hetero aggregation, dissolution, and sulphidation. These transformations largely depend on the characteristics of the nanomaterial like size and surface coating, as well as the nanomaterial’s interact with various environmental components, such as water, soil, and living organisms which also determined largely on the surface chemistry of the nanomaterial. For a scientifically sound risk assessment, tailored methods should be developed by the manufacturers or other responsible entities based on specific application scenarios.

174Based on the mechanisms outlined above, we recommend the following guidelines for medical product manufacturers conducting risk analysis of nanotechnology-derived medical products:pay higher attention to NPs due to their higher mobility;carefully consider the surface properties of all materials. For example, a nano-structured coating might not release NPs but could still pose cytotoxicity through physical interaction mechanisms when in direct contact;when evaluating the properties of a nanotechnology-derived medical product, especially the nanoscale materials it might contain or produce throughout its lifecycle (such as size, size distribution, surface modification, redox potential, etc.), remember that no universal rule has been established. Therefore, a characterisation protocol based on scientific rationale is necessary for both documentation and result reliability;for designing a reasonable characterisation protocol, refer to relevant technical manuals. However, these manuals are just a starting point aimed at distinguishing “normal bulk materials” from “nanomaterials” to facilitate future evaluation. Medical product manufacturers should thoroughly scrutinise their product;.regardless of the characterisation results, they only serve as input data for further toxicity or safety evaluation rather than as rigid indicators. For example, a material with nanoscale dimensions does not unconditionally show higher toxicity than its bulk form;the nano-safety risks associated with nanoscale materials or other forms of products involving nanotechnology can be analysed or controlled using the mechanisms outlined above.

175pay higher attention to NPs due to their higher mobility;

176carefully consider the surface properties of all materials. For example, a nano-structured coating might not release NPs but could still pose cytotoxicity through physical interaction mechanisms when in direct contact;

177when evaluating the properties of a nanotechnology-derived medical product, especially the nanoscale materials it might contain or produce throughout its lifecycle (such as size, size distribution, surface modification, redox potential, etc.), remember that no universal rule has been established. Therefore, a characterisation protocol based on scientific rationale is necessary for both documentation and result reliability;

178for designing a reasonable characterisation protocol, refer to relevant technical manuals. However, these manuals are just a starting point aimed at distinguishing “normal bulk materials” from “nanomaterials” to facilitate future evaluation. Medical product manufacturers should thoroughly scrutinise their product;.

179regardless of the characterisation results, they only serve as input data for further toxicity or safety evaluation rather than as rigid indicators. For example, a material with nanoscale dimensions does not unconditionally show higher toxicity than its bulk form;

180the nano-safety risks associated with nanoscale materials or other forms of products involving nanotechnology can be analysed or controlled using the mechanisms outlined above.

181Previous reviews have highlighted that key regional and national regulatory agencies have been proactively engaging in the oversight of nano-enabled products and collaborating to form a global consensus on standardisation and regulation. Initiatives aimed at the evaluation and regulation of nanomaterials have been launched by Europe, the United States, and China.

182In 2003, the United States officially proposed examining the possible impacts of synthetic nanomaterials on human health and the environment. By 2004, the Environmental Protection Agency (EPA) in the United States had established the direction for environmental and health safety research concerning synthetic nanomaterials, focusing on their environmental distribution, movement, and transformation, as well as their toxicological attributes. In 2007, the EPA in the United States released the Nanotechnology White Paper, which comprehensively addressed the risks to ecological toxicity and human health presented by synthetic nanomaterials. Following this, in 2009, the EPA issued the “Nanomaterials Research Strategy,” aimed at guiding scientists and regulatory bodies in investigating the possible environmental and health hazards associated with synthetic nanomaterials. In 2011, the President's Office along with the National Science and Technology Council released a White paper titled “Nanotechnology Environment, Health, and Safety Research Strategy,” incorporating nanotoxicology into the national research agenda. In the same year, the FDA published preliminary guidance to assist companies in determining the applicability of nanomaterials to their products.

183The European Union has also conducted research on the environmental and biosafety assessments of synthetic nanomaterials. In 2005, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) of the European Commission released “Artificial Products and by-products of Nanotechnology,” providing a systematic review of the toxicity, environmental impacts, and potential health dangers posed by nanomaterials.

184In 2007, discussions commenced in Europe regarding the adaptation of the existing REACH regulation (Registration, Evaluation, Authorisation, and Restriction of Chemicals) for application to nanomaterials. Moreover, the updated European cosmetic regulations mandated that starting from 2013, any products containing synthetic nanomaterials must clearly label them as such.

185Overall, for regulatory purposes, an initial clear definition was necessary. Factors to be considered in defining nano include: (i) size, (ii) size distribution, (iii) specific surface area, (iv) surface modification, (v) other physicochemical properties, (vi) whether the nanomaterials are organic or inorganic, (vii) nanocomposites, (viii) durability, (ix) whether the nanomaterials are manufactured or natural.

186Size is considered the primary criterion when defining nanomaterials. The European Commission Recommendation from 10th June 2022, regarding nanomaterial definitions, reinforces this by adhering to the 2010 SCENIHR opinion, defining 'nanoscale' as ranging from 1 to 100 nm. Similarly, the FDA's 2014 Guidance for Industry on nanotechnology applications specifies that for a product to be considered under nanotechnology, it should be engineered with at least one dimension, or have internal or surface structures, within the nanoscale range of approximately 1 nm to 100 nm. Additionally, the NMPA's 2021 Guiding Principles for medical devices using nanomaterials describe nanomaterials as having any external dimension or internal/surface structure in the nanoscale, specifically between 1 and 100 nm, a range which often, but not always, presents unique properties not seen in larger scales. Despite the global consensus on the 100 nm threshold, it is emphasised that this measurement is a guideline rather than a strict indicator of toxicity or safety. Materials smaller than 100 nm are not inherently toxic, nor are those larger necessarily safe. As stated in the “Scientific Basis for the Definition of the Term ‘Nanomaterial’”, the term ‘nanomaterial’ simply refers to a material categorised by the size of its parts and does not inherently indicate a specific risk or hazard. The designation ‘nano’ does not automatically mean the material possesses novel properties compared to its larger or smaller counterparts. However, the size of a material does affect its biodistribution and distribution kinetics within organisms and ecosystems, a statement that is widely agreed upon in the scientific community.

187This leads to a secondary criterion for defining nanomaterials, the “change of physicochemical properties”. Both the FDA and NMPA guidelines address whether a material or finished product is designed to demonstrate properties or effects, including physical, chemical, or biological, attributable to its dimensions, even if these dimensions are beyond the nanoscale range, extending up to one micrometer (1000 nm).

188However, it seems the EU regulatory body has not set a similar standard, which we believe is due to an intentional emphasis on NPs rather than nanostructures, such as coatings, as indicated in clause 11: “The definition should not apply to large, solid products or components, even when they possess an internal or surface structure at the nanoscale, such as coatings, some ceramic materials, and complex nanocomponents, including nanoporous and nanocomposite materials.” This implies that while there is a consensus on the nano dimension being defined as 1 to 100 nm, regulations across different regions are not completely aligned regarding whether zero-dimensional (e.g., QDs), one-dimensional (e.g., nanotubes, nanofibers), or two-dimensional (e.g., surface coatings with nano thickness or dispersed nanosheets) materials should be uniformly regulated under the same criteria or framework.

189Currently, among the various parameters considered for defining nanomaterials, the size requirement has been commonly addressed in many regions, whilst the EU has uniquely mentioned the specific surface area as a reference, and the FDA and NMPA have highlighted unique physicochemical properties. Another aspect that requires clarification is whether the materials are “manufactured or incidentally produced”. The EU’s Clause 6 expressly states that the nanomaterial definition should encompass natural, incidental, or manufactured materials, mirroring the stance in China where NMPA includes incidental nanomaterials under its regulatory framework. Conversely, the FDA’s guidelines specifically employ the term “engineered” to differentiate between deliberately modified nanotechnology products and those that might inadvertently contain nanoscale materials, pointing out that incidental NPs in conventionally manufactured products fall outside the scope of the guidance. It is also noteworthy that ISO 80004 series standards are dedicated to engineered nanotechnologies, including coatings among others.

190As of now, there are noticeable differences and ambiguities in the regulatory boundaries of nanotechnology, which could lead to confusion among companies without a solid scientific background, relying solely on regulatory texts. Nevertheless, a definitive compilation of terms would still be beneficial. The Joint Research Centre of the European Commission provides a summary of the core elements found in nanomaterial definitions across global organisations, and an analysis illustrating the similarities and distinctions in the regulatory definitions of nanomaterials across Europe, the United States, and China, and other major nations is presented in Fig. 34.

191Although regulatory stipulations vary from one nation to another, this does not imply that potential risks, such as nano-structured coatings in the EU or accidentally produced NPs in the US, should be disregarded; instead, these should be addressed through a framework designed for risk analysis papers. In fact, a case-by-case methodology for the safety evaluation and risk assessment of nanomaterials has been advocated by various authorities (EFSA in 2009, FDA in 2007, SCENIHR in 2009), since deducing risks from one nanomaterial to another is not deemed practical, even if they share the same basic chemical composition. The provision of our interpretation of both the scientific basis and the regulations is aimed at assisting companies and professionals in acquiring a more defined direction for this type of risk assessment.

192In the field of medicine and medical device registration, the adoption of a harmonised biological risk evaluation framework based on ISO 10993, which prioritises a risk-analysis approach over rigid testing protocols, indicates that the absence of precise definitions is unlikely to impede the innovative use of nanotechnology in the development of global healthcare products. For the safety assessment of specific nanomaterials, the European Parliament's REACH framework provides a versatile method for hazard evaluation and risk characterisation, making it particularly suitable for nanomaterials. REACH also promotes the use of computational methods, such as Quantitative Structure–Activity Relationships (QSARs), which has facilitated significant advancements in risk assessment despite the scarcity of experimental data. Moreover, the regulatory landscape is progressively aligning with the view that vertebrate animal testing should be employed only as a last resort, advocating for alternative testing approaches. However, to further enhance regulatory frameworks, there is a critical need to develop standardised nanomaterial characterisation data, employing harmonised testing standards and ensuring consistent reporting of endpoints. Currently, the availability of test data from the industrial sector is constrained by financial limitations and technological competition.

193To improve the regulatory framework for nanomaterials globally, it is crucial to implement several key strategies that enhance clarity, consistency, and scientific rigor. First, establishing a unified global database for nanomaterials would facilitate the consolidation of definitions, classifications, uses, and risk assessments from different regions. Such a database would provide a centralised resource that fosters information sharing and regulatory harmonisation, enabling companies to better navigate and comply with various regional regulations. Second, developing standardised tools and methods for the risk assessment of nanomaterials is essential. Standardisation would not only streamline the evaluation processes across different regulatory bodies but also ensure that risk assessments are comparable and consistent globally. This would help mitigate discrepancies in regulatory practices and provide a more coherent approach to understanding and managing the potential risks associated with nanomaterials. Third, introducing a dynamic regulatory mechanism that evolves in response to technological advancements and emerging scientific research is vital. Regulations should be adaptable to accommodate new findings and innovations in nanotechnology, ensuring that they remain relevant and scientifically sound. This approach would prevent regulations from becoming outdated and inadequate, thus maintaining a high standard of safety and efficacy. Fourth, promoting interdisciplinary research collaboration is necessary for a comprehensive understanding of nanomaterials' behaviour and their potential environmental and health impacts. By integrating insights from fields such as chemistry, materials science, biology, and toxicology, regulatory strategies can be more effectively tailored to address the complex nature of nanomaterials. Finally, developing clear guidance documents and technical standards would address current ambiguities within existing regulations. This includes providing explicit definitions and regulatory requirements for incidentally produced nanomaterials, which would reduce confusion among companies and ensure a more straightforward interpretation of regulations.

194Implementing these improvements would enhance the efficiency and effectiveness of nanomaterial regulation, fostering safer and more sustainable development of nanotechnology on a global scale.

195Nanotechnology is based on a variety of materials including organic, inorganic, carbon-based, and composite. As dimensions are reduced to the nanometer scale, materials scientists provide a range of design options such as discrete particles, unique shapes, or nanostructured coatings, among others. These designs showcase distinctive benefits as innovative nanomedicines, functioning as drug carriers or therapeutic agents, or when incorporated to improve the performance of NMDs, such as enhancing detection capabilities, antibacterial properties, and so forth. Yet, when entering the market, a comprehensive examination of product lifecycle risks associated with nanotoxicity reveals numerous safety concerns, and the potential mechanisms were explored here.

196The safety risks associated with nanotechnology in healthcare are multifaceted, often influenced by factors such as surface reactivity, size, and shape of nanomaterials. These same attributes, crucial for the efficacy of nanomedicine, also pose potential safety hazards. Understanding and addressing these risks require a focus on surface characteristics and their deviations from the original state.

197Environmental considerations are paramount throughout the lifecycle of nanotechnology products. While traditional hazard evaluation methods can be adapted for nano-specific aspects, the aging process of nanomaterials significantly impacts their environmental fate, emphasising the need for comprehensive assessments.

198Moreover, the complex nature of nanomaterials necessitates tailored risk assessments that account for individual material properties and toxicological profiles. A nuanced approach, aligned with regulatory standards, would enhance risk management strategies and ensure the responsible use of nanotechnology in healthcare.

199The evolution of nanotechnology in healthcare underscores the critical need for close collaboration among researchers, industry professionals, regulatory bodies, and healthcare practitioners. Successfully translating research advancements into market-ready applications requires prioritizing comprehensive risk assessment strategies, particularly with regard to long-term toxicity, which remains both the costliest and most critical aspect. Given the complexity of this research area, advancing the safe and effective integration of nanotechnology into healthcare hinges on robust interdisciplinary collaboration. By working together, we can harness the transformative potential of nanotechnology while safeguarding human health and environmental sustainability. This will involve the development of a more comprehensive regulatory framework, informed by cutting-edge scientific insights and supported by transparent communication across all sectors. Through these efforts, we can ensure the safe, effective, and sustainable deployment of nanotechnology in healthcare.