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Nucleic acid drugs: recent progress and future perspectives

Xiaoyi Sun, Sarra Setrerrahmane, Chencheng Li and 2 more

Signal Transduction and Targeted Therapy · 2024 · Review · CC BY

doi:10.1038/s41392-024-02035-4

Abstract

High efficacy, selectivity and cellular targeting of therapeutic agents has been an active area of investigation for decades. Currently, most clinically approved therapeutics are small molecules or protein/antibody biologics. Targeted action of small molecule drugs remains a challenge in medicine. In addition, many diseases are considered ‘undruggable’ using standard biomacromolecules. Many of these challenges however, can be addressed using nucleic therapeutics. Nucleic acid drugs (NADs) are a new generation of gene-editing modalities characterized by their high efficiency and rapid development, which have become an active research topic in new drug development field. However, many factors, including their low stability, short half-life, high immunogenicity, tissue targeting, cellular uptake, and endosomal escape, hamper the delivery and clinical application of NADs. Scientists have used chemical modification techniques to improve the physicochemical properties of NADs. In contrast, modified NADs typically require carriers to enter target cells and reach specific intracellular locations. Multiple delivery approaches have been developed to effectively improve intracellular delivery and the in vivo bioavailability of NADs. Several NADs have entered the clinical trial recently, and some have been approved for therapeutic use in different fields. This review summarizes NADs development and evolution and introduces NADs classifications and general delivery strategies, highlighting their success in clinical applications. Additionally, this review discusses the limitations and potential future applications of NADs as gene therapy candidates.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1The central dogma of genetics posits that nucleic acids carry human genetic information and play a crucial role in life processes, such as growth, development, and reproduction. Moreover, nucleic acids can be used to modify genetic information to treat various diseases., With the advancement of the life sciences, proteomics, and genomics methods, nucleic acid drugs (NADs) have been developed to translate and regulate nucleic acid functions.– These drugs can achieve long-lasting efficacy through gene repression, replacement, and editing., Many studies have shown the feasibility of NADs in disease prevention and treatment.– Thus, research and development on new classes of functional NADs are gradually emerging.

2NADs are a class of gene therapy agents based on DNA, RNA, or synthetic oligonucleotide analogs. They have considerable potential for clinical applications, such as treating bacterial infections, tumors, and neuromuscular diseases.– However, as negatively charged biological macromolecules, NADs have difficulty in crossing cellular membranes to enter cells. Additionally, they can be easily degraded by endogenous nucleases in plasma and tissues. Furthermore, few amounts of NADs that enter cells often become trapped by endosomes and subsequently degraded by lysosomes, considerably limiting their development and application.– Currently, two main strategies exist to address the application challenges of NADs. One approach is to modify the nucleic acid structure to stabilize the properties of NADs and avoid recognition by the immune system. The other approach is to use delivery systems that facilitate their passage through cell membranes and ensure their localization to specific subcellular compartments. Consequently, the modification and transformation of NADs and the development of efficient, safe, and targeted delivery systems have become the primary focus of research and development on NADs.,

3The accelerated development of the NADs field has relied on innovations and breakthroughs in foundational technologies, such as chemical synthesis, site-specific modifications, and delivery techniques. These advancements are crucial to ensure the safety, effectiveness, targeting, and applicability of NADs., Advancements in carrier technology and delivery systems have enhanced the biological activity of NADs, which improves their cellular targeting and uptake. Thus, the concentration and bioavailability of these drugs in target tissues are increased. Various delivery systems for NADs have been developed, including lipid nanoparticles (LNPs), cationic polymer complexes, and ligand-mediated nucleic acid molecular targeted delivery systems based on specific receptors, peptides, and other engineered carriers.– However, these systems have several drawbacks, such as nonspecific distribution, inefficient cytoplasmic delivery, and suboptimal organelle targeting. Several studies have reported that more than one strategy is needed to address the delivery challenges. Thus, combining chemical structure modifications of nucleic acids with advanced drug delivery systems could achieve enhanced therapeutic effects.

4This paper outlines the history of several significant molecular biology discoveries related to NADs, tracing key milestones from initial conceptualization to clinical applications. Then, we introduce the various NAD types and their modes of action, with an overview of both approved NADs and those currently in clinical trials. Then, we discuss the challenges associated with NADs development and explore strategies for overcoming the obstacles to in vivo delivery, including chemical modifications and delivery systems. Finally, we highlight the remaining challenges for NADs development, offering references for the design and clinical application of novel NADs.

Concept and historical development of NADs

5NADs development is inseparable from the major discoveries in fundamental molecular biology and the continuous observations of life activities (Fig. 1). In 1869, Friedrich Miescher discovered a new molecule called “nuclein” from white blood cells, which marked the beginning of DNA discovery. However, owing to the lack of advanced technologies at the time, the critical role of nucleic acids was not fully understood. The subsequent revelation of DNA’s double helix structure and the formulation of the central dogma of genetics clarified that nucleic acids are crucial participants in transmitting genetic information., Since then, researchers have understood that genetic information is encoded within nucleic acids and translated into proteins via complex mechanisms, and it plays a vital role in all life processes, such as growth, development, and reproduction.

6Additionally, there have been significant breakthroughs in NADs development including the discovery of RNA’s double-stranded structure and the phenomenon of nucleic acid hybridization. Early studies posited that single-stranded RNA could not form double-stranded structures. However, in 1956, Rich and Davies discovered that RNA could form double-stranded structures similar to those of DNA based on the principle of complementary base pairing. This result laid the foundation for developing RNA double-stranded drugs, including microRNAs (miRNAs) and small interfering RNAs (siRNAs). In 1960, Rich reported the phenomenon of DNA/RNA hybridization. In 1978, building on this discovery, Zamecnik and Stephenson used specific oligodeoxynucleotide chains that target the 35S RNA of the Rous sarcoma virus to inhibit virus replication, marking a prototype for the application of antisense oligonucleotide (ASO) drugs in disease treatment. As research on transcription and translation advanced, it was discovered that initial RNA transcripts typically require intron removal and the linkage of exons to form mature messenger RNA (mRNA), a process known as RNA splicing., RNA splicing is a crucial step in gene expression, and abnormalities in this process are the main cause of genetic variations and diseases., Dominski et al. found that ASOs targeting splicing sites can restore correct splicing of defective genes rather than only downregulating gene expression. This discovery provided a novel treatment strategy for diseases related to mis-splicing.

7In 1998, Andrew Fire and Craig Mello reported that double-stranded RNA (dsRNA) had potent gene silencing effects in Caenorhabditis elegans, a discovery they termed RNA interference (RNAi). RNAi was quickly applied to inhibit the replication of the hepatitis C virus in mice, marking the earliest evidence of siRNA-mediated in vivo gene silencing. In 2006, they were awarded the Nobel Prize in Physiology and Medicine for their RNAi technology. Subsequently, researchers demonstrated that siRNA could be tailored to disrupt the expression of any pathogenic gene, propelling RNAi into the spotlight and fostering its active application in the treatment of various diseases. In 2010, the first human trial using RNAi technology was conducted to evaluate the therapeutic effect of siRNA for targeting the M2 subunit of ribonucleotide reductase in patients with melanoma. Since then, siRNA drugs have had issues with stability, immunogenicity, off-target effects, safety, and the delivery system. However, after advanced chemical modifications and the development of targeted delivery systems, the first siRNA drug approved by the Food and Drug Administration (FDA) in 2018 reignited interest in NADs.

8Notably, the discovery of RNA-dependent RNA polymerase and reverse transcriptase has been crucial for developing subsequent mRNA drugs., In 1984, Krieg and Melton used RNA polymerase extracted from viruses for in vitro transcription from engineered DNA templates, successfully achieving mRNA expression in cell-free systems. Thus, since the 1990s, in vitro-synthesized mRNA has been increasingly applied for protein replacement in preventive and therapeutic vaccines.– In 2005, the discovery of pseudouridine (Ψ) modification addressed the immunogenicity issue of in vitro-synthesized mRNA, leading to the initiation of the first human trial of an mRNA vaccine against melanoma in 2008. In 2020, during the COVID-19 pandemic, the FDA authorized the emergency use of mRNA vaccines, providing effective measures for preventing and controlling the virus., This resulted in widespread public attention to NADs. In 2023, the Nobel Prize in Physiology and Medicine was awarded to Katalin Kariko and Drew Weissman for pioneering nucleoside base modification technology to decrease mRNA immunogenicity, further highlighting the critical role of chemical modification technologies in developing mRNA vaccines. This opened new clinical applications for NADs in treating human diseases.,

9Simultaneously, discovering other types of nucleic acids and biological phenomena has further expanded the scope of NADs. Specifically, the emergence of gene-editing technology has provided a foundation for developing new therapies for genetic mutation diseases.– Recently, the first gene therapy based on clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology has been approved for marketing, resulting in revolutionary changes in NADs development.

Classification and therapeutic mechanisms of NADs

10NADs can be broadly divided into three categories based on their mechanisms of action. The first category includes NADs that target nucleic acids to regulate protein expression by promoting or inhibiting translation. This category primarily consists of ASOs, siRNAs, miRNAs, small activating RNAs (saRNAs), and the CRISPR/Cas system, which enables precise gene editing of genomic DNA.

11The second category includes NADs that target proteins, with aptamers as the main examples. Unlike the first category, aptamers can directly and specifically bind to target proteins, functioning similarly to antibodies by providing a targeting mechanism.

12The third category includes NADs that express proteins, such as in vitro-transcribed mRNA, which can produce specific proteins in vivo to exert biological activity. This section briefly introduces the mechanisms of action of these different NAD types and highlights drugs successfully applied in clinical settings (Fig. 2).

ASOs

13ASOs are artificially synthesized single-stranded oligonucleotide chains that regulate and target RNA’s function via specific binding according to the Watson-Crick base-pairing principle. The mechanisms of action of clinically used ASOs mainly include ribonuclease H (RNase H)-mediated degradation (Fig. 2a) and steric blockage mechanisms (Fig. 2b).– RNase H-dependent ASOs, such as gapmers, bind to complementary mRNA, recruit RNase H to cleave mRNA, and thus block translation of the target gene. This results in the inhibition or reduction of the synthesis of the target protein. Representative drugs based on this mechanism include fomivirsen (Vitravene®), mipomersen (Kynamro®, Delisted), inotersen (Tegsedi®), volanesorsen (Waylivra®), and tofersen (Qalsody®).– Because RNase H is active in the nucleus and cytoplasm, ASOs can also target other transcripts, such as long non-coding RNAs., Indeed, the pathogenesis of many diseases without clear protein targets is related to non-coding RNA, which can be used to predict the advantages of ASO in treating diseases.,

14Additionally, ASOs can form a double-stranded structure complementary to miRNA, leading to its degradation and causing gene upregulation.– Additionally, ASOs regulate transcription via steric hindrance, influencing specific splicing of pre-mRNA and selectively altering the expression of specific proteins., ASOs that employ this mechanism are splicing-switching oligonucleotides, which modulate functional target gene expression by skipping or including exons.– For example, Golodirsen, an ASO drug targeting the human Duchenne muscular dystrophy (DMD) gene, was introduced in the USA in 2019 by Sarepta Therapeutics to treat DMD patients with confirmed mutations amenable to exon 53 skipping. Additionally, several studies have demonstrated that ASOs can disrupt translation initiation by targeting and masking the AUG start codon of the target mRNA. These discoveries have enabled ASOs to be applied in disease treatment via more diverse mechanisms.

siRNA

15siRNA is a dsRNA molecule that is typically 19–23 base pairs long and is found naturally in various organisms or artificially synthesized., As a classical effector of RNAi, siRNA induces gene silencing by blocking mRNA translation., Unlike ASOs, siRNA-mediated gene silencing occurs via the RNA-induced silencing complex (RISC), not RNase H. Once mature siRNA enters the cell, it forms a complex with the Argonaute-2 (AGO2) protein (Fig. 2c)., As the passenger strand of siRNA is degraded, the antisense strand binds to the target mRNA. It guides RISC to cleave the target sequence, thus achieving therapeutic effects by downregulating the translation of specific proteins.– Based on this mechanism, researchers have designed siRNAs that target specific pathological genes to achieve specific gene silencing using RNAi., However, challenges, such as stability, specificity, and delivery obstacles, hindered progress in the early stages of development.– Advancements in carrier technology and nucleic acid modification techniques have led to significant progress in overcoming these challenges, as exemplified by the first siRNA drug, patisiran (Onpattro®), which has been approved for treating hereditary transthyretin-mediated amyloidosis by degrading mRNA encoding transthyretin (TTR). Thus far, six siRNA drugs have received international approval. With the ongoing development of novel chemical modifications and targeted delivery systems, more siRNA drugs are anticipated to enter the market soon.

miRNA

16Endogenous non-coding RNAs that have been discovered in eukaryotic organisms can act as gene regulators. Since the 1993 discovery of the first miRNA, lin-4, in the nematode C. elegans, miRNAs have been shown to participate in various biological functions and pathological mechanisms, including cell proliferation, differentiation, migration, disease occurrence, and progression. There has been extensive research on the regulatory mechanisms of miRNAs. With the assistance of complexes, such as Drosha/DGCR, Exportin-5/RAN-GTP, and Dicer/TRBP, primary miRNAs (pri-miRNAs) transcribed from the non-coding region of miRNA genes are processed to form mature miRNAs (Fig. 2d).– miRNAs combine with Argonaute proteins to form the miRNA-induced silencing complex (miRISC), which can silence the target transcript via base pair complementation., Unlike siRNA-mediated gene silencing, miRNAs can simultaneously recognize and regulate the expression of multiple target mRNAs due to their low complementarity., The antisense strand of miRNA can bind to the target mRNA via complete and incomplete complementarity, leading to the cleavage of target mRNA and the inhibition of target gene expression., Contrary to the classical gene silencing mechanism, research has shown that miRNAs can interact with 3’-UTR to upregulate gene expression, indicating the complexity and diversity of miRNA regulatory mechanisms.–

17As studies on the roles of miRNAs in diseases continue to be reported, there is anticipation for the potential use of miRNAs in different pathological processes. However, thus far, no miRNA drugs have been approved for the market., miRNA drugs’ ongoing development primarily includes two categories: miRNA mimics and miRNA inhibitors.– miRNA mimics are synthetic dsRNA molecules that mimic the function of endogenous miRNAs. Similarly, miRNA inhibitors are single-stranded RNAs that are complementary to endogenous miRNAs, which can reduce the effect of gene silencing by specifically inhibiting miRNA., The miRNA drug MRG-201 (Remlarsen), developed by Viridian Therapeutics (formerly known as miRagen Therapeutics), simulates microRNA-29b to reverse regulate fibrosis, thus inhibiting fibrous proliferation in skin wounds. Clinical trials have been conducted to evaluate the efficacy and safety of MRG-201 in treating fibrotic diseases (NCT03601052). In addition to MRG-201, Viridian Therapeutics has several other miRNA-based drugs, including MRG-106 (Cobomarsen), which targets miR-155 to inhibit tumor development, and MRG-110, which targets microRNA-92 to promote angiogenesis., TTX-MC138 (NCT06260774 and NCT05908773), designed by TransCode Therapeutics, targets microRNA-10b in the treatment of pancreatic cancer. Despite the relatively slow progress in miRNA-related drug development compared with other NADs, their superior performance in treating tumors, heart failure, and diabetes indicates their promising prospects in clinical treatment.

saRNA

18In addition to the classical gene silencing mechanism, the discovery of RNA activation has provided a new perspective on gene regulation. RNA activation is a gene regulation phenomenon mediated by a small dsRNA called saRNA, which targets gene promoter sequences to enhance the transcription of the target gene., After entering the cell via endocytosis, saRNA binds to AGO2. The sense strand is released and degraded, as AGO2 and the antisense strand are transported into the cell nucleus, where they bind to the promoter region (Fig. 2e). Subsequently, AGO2 recruits RNA polymerase-associated protein CTR9 homolog (part of the polymerase-associated factor 1 complex) and RNA helicase II (RHA) to form the RNA-induced transcriptional activation (RITA) complex. This complex interacts with RNA polymerase II (RNAP II) and stimulates the initiation and elongation of transcription., saRNAs are conserved in mammals and participate in the activation of various genes, such as vascular endothelial growth factor A (VEGFA), E-cadherin, progesterone receptor, and Kruppel-like factor 4.,– This conservation allows for the establishment of animal models and preclinical studies for saRNA-based therapies. Targeted activation therapy using saRNA has been validated in various disease animal models.,– However, clinical translation of saRNAs remains challenging due to the absence of an immune system in xenograft models and the complexity of drug action in the human body.

19The leading saRNA drug, MTL-CEBPA, which was developed by MiNA Therapeutics, targets the CCAAT/enhancer-binding protein alpha (CEBPA). Phase I trial results (NCT05097911) have demonstrated that MTL-CEBPA has a good safety profile for the treatment of hepatocellular carcinoma and may enhance the therapeutic effects of tyrosine kinase inhibitors by modulating immune suppression.– In addition to MTL-CEBPA, MiNA Therapeutics has several saRNA candidates in preclinical development for undisclosed tumor types, metabolic diseases, and genetic disorders. RAG-01 is another saRNA candidate drug designed to treat bladder cancer by activating the expression of the human cyclin-dependent kinase inhibitor 1 A. Ractigen Therapeutics has submitted an Investigational New Drug application for RAG-01, and it is expected to become the second saRNA drug to enter clinical trials internationally.

CRISPR/Cas9 system

20Gene editing is a genetic engineering technology that precisely modifies target genes via insertion, deletion, and site-specific mutation. The CRISPR/Cas9 system has gained widespread attention among the various genome-editing methods. As a prokaryotic adaptive immune system, CRISPR/Cas modules establish bacterial defense against exogenous nucleic acids. They have been widely used in gene editing owing to their high efficiency and accuracy.– The CRISPR-mediated gene-editing system primarily involves Cas9 and single guide RNA (sgRNA) to introduce DNA double-strand breaks (DSBs) at specific positions in the genome. These DSBs are usually repaired by homologous directed repair (HDR) or nonhomologous end joining (NHEJ), achieving mutation or foreign gene insertion (Fig. 2f)., CRISPR/Cas9 technology has been effective in various fields, including hematologic disorders, malignant tumors, and genetic diseases.– However, this technology has several challenges, such as low delivery and HDR efficiency, off-target effects, and toxic side effects.– Currently, the CRISPR/Cas9 system can enter cells for gene editing in three forms: the Cas9: sgRNA ribonucleoprotein complex, mRNA for Cas9 translation alongside a separate sgRNA, and a DNA plasmid that encodes both the Cas9 protein and sgRNA.– Each method has its pros and cons. The plasmid system is relatively stable but has low cutting and editing efficiency, and continuous expression of Cas9 may increase off-target effects. mRNA and sgRNA are susceptible to degradation by nucleases. The Cas9/sgRNA ribonucleoprotein complex, while the most responsive mode of action, has a low off-target rate and low toxicity, but the large size of the complex complicates delivery. The delivery of the CRISPR/Cas9 system is a crucial issue limiting its clinical application. Like other NADs, researchers have focused on nanocarriers based on liposomes, chitosan, and other materials to achieve efficient delivery, laying a solid foundation for the clinical application of the CRISPR/Cas9 system.– Exa-cel (Casgevy®) was approved in November 2023 as the first gene-editing therapeutic drug based on the CRISPR/Cas9 system for treating sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). Exa-cel stimulates artificial blood stem cells and progenitor cells in vitro to differentiate into red blood cells that produce high fetal hemoglobin levels., The launch of Exa-cel has filled the gap in gene-editing drugs and provided considerable motivation for developing other gene-editing therapies.

NADs that target proteins

21Aptamers are single-stranded oligonucleotide molecules that have specific recognition functions obtained via iterative screening from large libraries of random oligonucleotides using the systematic evolution of ligands by exponential enrichment (SELEX) technology.– Unlike other nucleic acid-based drugs, aptamers specifically recognize and bind target molecules, such as peptides, proteins, viruses, bacteria, and cells, relying on their unique three-dimensional conformation. This is similar to the conformational recognition that mediates antibody–antigen interactions and complex formation (Fig. 2g).– However, compared with antibodies, aptamers have several advantages, including high thermal and physiological stability, low immunogenicity, and a wider range of target specificity. Since their first report in 1990, SELEX technology has been continuously improved,, diversifying the selection and development of high-affinity aptamers., Aptamers have shown promising applications in treating cancer and ophthalmic and cardiovascular diseases (CVDs).–

22In 2004, the FDA approved the first aptamer drug, pegaptanib (Macugen®), to treat choroidal neovascularization caused by neovascular age-related macular degeneration (AMD). However, Pegaptanib was withdrawn from the market owing to its poor efficacy and competition from anti-VEGF antibody drugs, such as Lucentis. Despite this, research on aptamers continues. In August 2023, avacincaptad pegol was approved for treating geographic atrophy (GA) secondary to dry AMD. Complex cascade overactivity is likely instrumental in AMD pathology. A crucial complement component, C5, has become a primary therapeutic target for many inflammatory diseases, including AMD. As a C5 inhibitor, avacincaptad pegol has been shown to slow GA progression by targeting the source of retinal cell death. Additionally, AS1411 is a candidate drug that targets nucleolin, which has been confirmed to be effective for treating renal cell carcinoma, glioma, and acute myeloid leukemia. In addition, aptamers are widely used in drug delivery, clinical diagnostics, and biosensing.– This paper primarily focuses on their application as therapeutic drugs. Thus, we will not describe their other uses in detail further.

NADs that express proteins

23mRNA, a single-stranded polynucleotide that carries genetic information, is essential for expressing encoded proteins within cells, thus exerting corresponding biological functions via these proteins. Consequently, the concept of using mRNA as NADs has been proposed. In 1990, Wolff et al. injected in vitro-synthesized mRNA into mouse skeletal muscle and successfully induced the expression of specific proteins. They demonstrated the feasibility of using in vitro-synthesized mRNA as an information carrier to guide somatic protein synthesis.

24However, the development of mRNA-based drugs has resulted in several challenges. Unmodified mRNA can induce Toll-like receptor-mediated immune responses, leading to blocked protein synthesis. Kariko and Weissman discovered that nucleobase modifications could protect mRNA from triggering inflammatory responses., In addition, the large size of mRNA and its susceptibility to degradation by nucleases result in low cellular uptake, further limiting its application. To overcome these obstacles, researchers have developed various delivery systems, including lipids, peptides, and polymers, for mRNA delivery both in vitro and in vivo.–

25In contrast to the previously mentioned NADs that exert therapeutic effects by directly binding mRNA or proteins, two strategies for the use of mRNA drugs have been attempted (Fig. 2h). One strategy is protein replacement therapy, which involves introducing exogenous mRNAs into cells to express functional proteins or supplement deficient ones., For example, one research group used LNPs to deliver mRNA encoding erythropoietin into mouse fetuses, thus increasing erythropoietin protein levels in the mouse bloodstream. Additionally, mRNA therapy has been applied to treat patients with deficiencies in essential enzyme genes, such as argininosuccinate lyase, ornithine transcarbamylase, and methylmalonyl-CoA mutase (MUT), therefore restoring enzyme levels and mitigating deficiencies.– Moderna, a company dedicated to mRNA therapy, has several mRNA drugs based on enzyme replacement therapy in clinical trials. For instance, mRNA-3927, which encodes the alpha and beta subunits of the propionyl-CoA carboxylase enzyme, is designed to treat propionic acidemia. A Phase I/II trial (NCT05130437) for this indication has been initiated in pediatric patients to evaluate the long-term safety of mRNA-3927. Additionally, mRNA-3704 and mRNA-3705 encode MUT, which is designed to treat methylmalonic acidemia and is currently under investigation.

26The second approach involves mRNA vaccines, which activate the body’s immune response to combat infectious diseases and tumors by directly translating mRNA-containing antigen proteins. Compared with traditional inactivated vaccines, mRNA vaccines have advantages such as cell-free production, high production efficiency, and low cost. Thus, they are quite promising for addressing sudden epidemic infectious diseases. During the COVID-19 pandemic, mRNA prophylactic vaccines were crucial among all candidate vaccine types. The FDA authorized the emergency use of BNT162b2, which was developed by Pfizer-BioNTech, and mRNA-1273, developed by Moderna., Moreover, the development of mRNA vaccine technology has been propelled by large-scale clinical trials of mRNA vaccines. For example, ARCov, which was jointly developed by Abogen Biosciences, the Academy of Military Medical Sciences, and Walvax Biotechnology, has addressed the issue of poor thermal stability of mRNA vaccines., Additionally, preventive vaccines against influenza viruses,, respiratory syncytial virus, rabies virus, and other viruses, as well as cancer-targeted therapeutic vaccines,– are being continuously researched and developed, which further reflect the application prospects of mRNA vaccines.

27In summary, in recent decades, NADs development has undergone significant progress and achieved considerable results. More than 20 products based on ASOs, aptamers, siRNA, and mRNA have been approved for marketing to treat various rare genetic disorders (Table 1). Several companies worldwide have been active in this field, attracting substantial investment, and the market development space is expected to expand further.

Current challenges in NADs development

28Unlike traditional small molecules and antibody drugs that exert their pharmacological effects on proteins, most NADs directly regulate gene expression, offering a broader range of targets. This is particularly valuable for addressing genes with defective proteins that are difficult to be targeted with conventional drugs, showing considerable potential in treating rare, chronic, infectious diseases and other metabolic disorders. Despite these advantages, researchers must accurately identify the genetic information related to the disease and choose the appropriate type of NADs based on the mechanism of action., For targeted NADs, including ASO and siRNA, when the relevant genetic information of the disease is determined, lead compounds can be designed for the gene sequence to avoid off-target effects during development. The efficacy of aptamer drugs is related to their sequence and conformation. SELEX technology has been applied to better screen specific sequences with high affinity for a target from a randomly generated single-stranded nucleic acid sequence library. Understanding the relationship between the mRNA sequence, structure, function, and stability for mRNA development is important to ensure the maximum functional protein output of delivered mRNA molecules. In recent years, the NADs sequence design process has been accelerated by the development of advanced bioinformatics tools, considerably reducing the time and costs.,,, Nonetheless, the major obstacle in NADs development involves how to reach target cells to fully achieve therapeutic benefits (Fig. 3).,, The most relevant challenges can be summarized as follows.

Pharmacokinetics, stability, and degradation

29Naked nucleic acids have poor in vivo stability and can degrade in the bloodstream. They undergo either enzymatic (nucleases and RNAse) or chemical (oxidation and hydrolysis) degradation in the blood and tissue fluids or are filtered and cleared by the kidneys. Researchers have implemented several chemical modifications to enhance NADs stability, but almost all these methods can affect the efficacy and safety.

Immunogenicity

30Exogenous nucleic acids can be recognized as exogenous signals by pattern recognition receptors in the immune system, triggering immune responses that compromise the structural integrity and stability of the nucleic acids. Careful design and modification of NADs can mitigate immunogenicity, but this requires extensive testing.,

Targeting problems

31Therapeutic nucleic acids often lack sufficient targeting ability in vivo. This insufficient targeting leads to low NADs concentrations at the disease site and unintended gene silencing or activation, potentially causing safety issues by requiring higher doses. Designing particular nucleic acids and conducting thorough off-target screening are critical for the efficient clinical application of NADs.

Uptake efficiency and endosomal escape

32Efficient uptake of NADs into cells is difficult owing to their size, charge, and hydrophilicity. Negatively charged nucleic acids do not easily cross the negatively charged lipid bilayer of the cell membrane. Additionally, endosomal escape is a significant barrier as nucleic acids often become trapped in endosomes and degraded. After entering cells, NADs are often captured by endosomes. Only those NADs that successfully escape the endosomes can exert their therapeutic effects. Inadequate endosomal escape can result in reduced efficacy and increased off-target toxicity.

33In addition to the previous issues, NADs face manufacturing and scalability challenges. Producing NADs at scale with consistent quality requires advanced manufacturing technologies and stringent quality control measures. This results in a relatively high cost, affecting accessibility and affordability for patients.

Strategies to improve NADs performance

34Because of these challenges, accurately delivering drugs to target tissues and improving patient quality of life have become the core objectives for NADs development and research. Recently, significant advancements have been made in chemical modification technologies and delivery vehicles for NADs, considerably enhancing delivery efficiency. Thus far, dozens of NADs have benefited from successful chemical modification and carrier delivery and have earned FDA approval. For example, the success of COVID-19 vaccines is mainly due to advancements in base modification and LNP delivery systems. Therefore, the focus of NADs research and development has shifted toward improving nucleic acid modifications and developing efficient, safe, and targeted delivery systems.

Chemical modification

35Various chemical modification methods have been introduced with the continuous progress of chemical synthesis and modification technologies to provide more precise treatments., NADs can be precisely modified to improve their efficacy and stability while decreasing toxicity and immunogenicity., The most widespread modification methods include backbone, ribose, and nucleobase modifications.–

Backbone modification

36The modification strategies used in first-generation NADs have focused on modification of the phosphate backbone, mainly using other types of groups to replace the non-bridging oxygen atoms in the phosphate backbone, such as phosphorothioate (PS), methyl phosphate, and boranophosphate. The most often used backbone modification method is PS modification, where the oxygen atom is replaced by sulfur. This modification can improve the resistance of nucleic acids to nucleases, enhance blood stability, reduce renal clearance, and prolong the circulation time of drugs in vivo by improving their binding to plasma proteins.– However, it has been determined that while improving stability, PS modification can induce inflammatory responses and produce hepatotoxic effects. Fomivirsen, a representative drug modified by PS, was withdrawn due to its limited therapeutic effect and inflammatory reaction. This has inspired the exploration of new modification technologies to reduce the adverse effects associated with PS modification.

Ribose modification

37Ribose modification is another common strategy that has had notable success. Changes to the 2’ position group can affect nucleic acid stability and affinity, with common modifications including 2’-fluoro (2’-F), 2’-O-methoxyethyl (2’-MOE), and 2’-O-methyl (2’-OMe).,, These modifications considerably increase nuclease tolerance and prolong the half-life of nucleic acids while effectively avoiding the inflammatory reactions triggered by PS modification, demonstrating a higher safety and activity. Furthermore, synergistic modifications combining PS and 2’-MOE have considerably improved the physicochemical properties and reduced NADs side effects. Dual modifications, such as 2’,4’- and 2’,5’-sugar modifications, have been employed in the development of siRNA therapeutics to further expand the potential of ribose modifications. Beyond specific site modifications, altering the sugar ring provides another NADs design strategy. A locked nucleic acid (LNA) is a nucleic acid analog with a unique bicyclic structure, where the C4’ and O2’ atoms are connected by different methylene bridges, forming a stable C3’-endo conformation. An LNA adheres to Watson-Crick base pairing and has a strong affinity for DNA and RNA. However, owing to its bicyclic backbone structure limitations, an LNA can only spontaneously form A-type hybrid duplexes with target nucleic acid strands., These hybrids have strong thermal stability and can activate RNase H degradation activity under specific conditions, indicating LNA’s potential as an antisense drug. Overall, LNA’s good stability, high binding specificity, and strong nuclease resistance make it advantageous for in vitro and in vivo applications. In contrast, unlocked nucleic acid (UNA) is a flexible RNA mimic that lacks chemical bonds between the ribose ring’s C2’ and C3’ atoms. A UNA can attach to oligonucleotide monomers to form hybrids, regulating their flexibility and thermal stability. A UNA supports RNase H activity, which is beneficial for antisense-based nucleic acid therapies. Additionally, UNA modification at the siRNA terminus improves siRNA stability and silencing efficacy while considerably reducing off-target effects, highlighting its potential in the development of new therapeutic siRNAs.,

Nucleobase modification

38Nucleobases are essential components of nucleic acids, and changes to their structure can affect the stability, biological activity, and immunogenicity of nucleic acids., By modifying specific sites on nucleobases, the stability and affinity of nucleic acids can be greatly improved. Canonical nucleoside analogs formed from nucleobase modifications include 5-methylcytidine (m5C), 5-fluorouracil (5-FU), N7-methylguanosine (m7G), pseudouridine (Ψ), N6-methyladenosine (m6A), and 2’-deoxy-2’-fluoro-uridine (2’-FU).– Modifications, such as m5C and Ψ, reduce the activity of cytokines and biomarkers in dendritic cells, helping mRNA evade the immune system.,, Yoshida et al. found that base modification could considerably reduce the hepatotoxicity of gapmer ASO, providing insights for developing new gapmer ASOs. Additionally, in RNAi processes, the 5’ nucleobase affects the binding activity of AGOs to siRNA, thus reducing target cleavage activity., Therefore, chemical modification at this specific position could improve siRNA binding affinity.

39Nucleic acid analogs offer new modification technologies, considerably enhancing the stability and reducing the immunogenicity of NADs in vitro and in vivo., Replacing the phosphate backbone by other group improves target affinity, nuclease resistance, and pharmacokinetic properties of nucleic acids. For peptide nucleic acids (PNAs), the sugar-phosphate backbone is replaced by a peptide backbone, which retains the specific binding ability with DNA/RNA and offers higher affinity and better stability than natural nucleic acids. Due to these backbone modifications, PNAs show improved resistance to nuclease and protease digestion. These characteristics make PNAs powerful tools for disease diagnosis and treatment., However, their poor distributions in vivo and low cellular uptake are challenges for their clinical application. Phosphorodiamidate morpholino oligonucleotides (PMOs) are another class of nucleic acid analogs with significant potential, which are characterized by a six-membered morpholine ring backbone. Several PMO-based NADs have been approved for treating DMD, including eteplirsen (Exondys 51®), golodirsen (Vyondys 53®), viltolarsen (Viltepso®), and casimersen (Amondys®)., Both PMOs and PNAs are neutral nucleic acid analogs with weak binding to plasma proteins, allowing them to be easily cleared by the kidneys. In practice, high doses are required to maintain the therapeutic effects, which can lead to corresponding toxicities and side effects.

LNPs

40LNPs are self-assembled nanostructures with diameters of approximately 100 nm, capable of combining with negatively charged nucleic acids through electrostatic interactions. They have been widely used for NADs delivery due to their excellent compatibility with cell membranes., Classical LNPs typically include ionizable lipids (ILs) or cationic lipids (CLs), auxiliary lipids, cholesterol, and Polyethylene glycol (PEGylated) lipids (Fig. 4a). These components self-assemble into monodisperse nanoparticles in specific proportions through intermolecular interactions, encapsulating NADs in their core to protect them from nuclease degradation during delivery. Furthermore, modifying the surface properties of LNPs can enhance the uptake by specific cells and alter the distribution of NADs.

41In early designs, CLs were permanently charged to bind the cell membrane and NADs effectively. However, their cytotoxicity limited their application in nanoparticle design., ILs are crucial for delivery efficacy, as they can encapsulate nucleic acids in LNPs while affecting the uptake and endosomal escape of NADs. ILs remain neutral at physiological pH, reducing the toxicity and immunogenicity of drugs. At low pH values, ILs acquire a positive charge, interacting with the negatively charged endosomal membrane and transforming its planar bilayer structure into a more hexagonal configuration. This transformation promotes the escape and release of NADs encapsulated in LNPs., 1,2-Dioleyloxy-3-dimethylaminopropane (DODMA) and its analog 1,2-dioleyloxy-3-(dimethylamino) propane (DODAP) were among the first ILs used for RNA delivery. Continuous optimization of ILs revealed that the pKa of ILs is a critical factor in delivery efficacy. An optimal pKa value of 6.2–6.5 maximizes NADs efficacy. Researchers have synthesized ILs, such as DLin-KC2-DMA and DLin-MC3-DMA, with the latter used as a novel component for encapsulating nucleic acids. DLin-MC3-DMA was integral to the development of the first FDA-approved siRNA drug, Onpattro®, and has been proven effective for mRNA delivery in vivo., In addition, this technology is used in the clinically approved vaccines ALC-0315 (BNT162b2-Comirnaty®) and SM-102 (mRNA-1273-Spikevax®), where the pKa value ranges from 6.1 to 6.7., Unlike DLin-MC3-DMA, these vaccines incorporate an ester-based structure in the hydrophobic tail of lipids, enabling faster lipid clearance and improving product tolerance.

42PEGylated lipids are another crucial component of LNPs that significantly influence their size, stability, and in vivo distribution. However, they have encountered several challenges.– PEG modification can inhibit the binding of apolipoprotein E to LNPs, a key mechanism for LNP uptake by the liver, thereby affecting liver uptake of LNPs. Moreover, repeated administration of PEGylated products may produce PEG antibodies, potentially reducing drug efficacy.,

431,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) are common helper lipids in commercially available LNPs. DSPC, a phospholipid molecule with a choline head group and two saturated octadecyl chains, is a critical excipient in Onpattro® and COVID-19 mRNA vaccines. Alternatively, DOPE disrupts the endosomal membrane structure by forming a hexagonal crystalline phase, facilitating the release of encapsulated RNA from endosomes. Addressing the limitations of traditional phospholipid structures, Liu et al. developed hundreds of ionizable phospholipids called iPhos, which were capable of promoting endosomal membrane fusion and inducing hexagonal phase transitions. Cholesterol possesses a strong membrane fusion capacity, facilitating the internalization of NADs and their entry into the cytoplasm. Studies indicate that apolipoprotein E can cause cholesterol to migrate from the core of LNPs to the outer lipid layer, potentially altering the surface properties of LNPs., Additionally, Siegwart’s team introduced the fifth component, selective organ targeting, to achieve precise and universal extrahepatic-targeted mRNA delivery strategies.

44Approximately 150 molecules employ LNP technology, with nearly 75% dedicated to delivering NADs in RNA therapy, including ASOs, siRNA, and mRNA., Several new RNA therapeutics are in late-stage clinical trials, such as mRNA-1944 (NCT03829384) and NTLA-2001 (NCT06128629). Vaccines, such as BNT162b2 and mRNA-1273, have been developed based on mRNA LNP technology against COVID-19, which demonstrate the feasibility of LNPs in delivering mRNA encoding the spike protein of syndrome coronavirus 2 (SARS-CoV-2), thus eliciting an immune response against the virus.

Cationic polymeric nanoparticles

45Delivery systems for NADs based on synthetic or natural cationic polymers are complex structures formed through electrostatic interactions between polymers carrying cationic groups and NADs. Upon cell internalization via endocytosis mechanisms, these nanoparticles disrupt endosomal membranes through the proton sponge effect, facilitating the intracellular delivery of exogenous nucleic acids. Various cationic polymers, including polyethylenimine (PEI), polyamidoamine dendrimers (PAMAM), poly-L-lysine (PLL), poly-β-aminoester (PBAE), and poly-lactic-co-glycolic acid (PLGA), have been developed for this purpose (Fig. 4b)., As a representative cationic polymer, PEI is widely used in non-viral gene vectors in linear PEI (LPEI) or branched PEI (BPEI)., BPEI exhibits stronger gene compression ability than LPEI due to its structure containing primary, secondary, and tertiary amine groups every two carbon atoms, enhancing electrostatic interactions with nucleic acids. With a molecular weight of 25 kDa, PEI is considered the “gold standard” for gene transfection due to its high efficiency, but it induces significant cytotoxicity and lacks biodegradability., PLL, another widely used cationic polymer, is synthesized through ring-opening polymerization of its monomers. Its positively charged amino acids interact electrostatically with the phosphate backbone of NADs, enabling the delivery of RNA and DNA., Despite the biodegradability and biocompatibility of PLL, its in vivo activity remains limited due to its high toxicity, low transfection efficiency, and poor endosomal escape ability. Functional modifications, such as chloroquine, histidine, PEG, or PEI, have been incorporated into PLL to address these limitations.,, Recent advancements include PLL nanoparticles coated with hyaluronic acid shells, significantly reducing cytotoxicity, enhancing cellular uptake, and improving gene expression.

N-Acetylgalactosamine (GalNAc)

46Most approved products based on bio-conjugated delivery systems use the GalNAc-coupled delivery system developed by Alnylam Pharmaceuticals. GalNAc, a carbohydrate compound, exhibits a high affinity for the asialoglycoprotein receptor (ASGPR). ASGPR is an endocytic receptor notably overexpressed on the hepatocyte membrane surface., Interaction between GalNAc and ASGPR facilitates the internalization of GalNAc-bound compounds from the cell surface into endosomes via clathrin-dependent receptor-mediated endocytosis. As the endosome matures and pH decreases, ASGPR dissociates from the GalNAc conjugate and recycles back to the hepatocyte surface.– At the same time, GalNAc is degraded, releasing NADs into the cytoplasm to initiate gene regulatory activity.

47Leveraging this mechanism, Alnylam has extensively explored GalNAc conjugation with NADs, particularly siRNA, to achieve liver-specific delivery (Fig. 4c).,, Notably, the nucleic acid molecules in these conjugates are directly exposed to serum; enhancing their stability in the physiological environment is a crucial challenge. Studies have demonstrated that stability can be significantly enhanced by extensive chemical modification at the 2’ position of nucleotide sugars and by replacing the phosphodiester bond with a thiophosphate bond.– Furthermore, stability can be improved without compromising drug activity by optimizing the number and modification positions of 2’-F and 2’-OME groups on both strands of double-stranded siRNA, leading to substantial efficacy improvements.,, These advancements have accelerated the shift from standard template chemistry to enhanced stability chemistry. Rapid ligand-receptor binding and efficient uptake by target cells are critical for receptor-targeted delivery systems to avoid in vivo clearance.,– Multivalent ligands show significantly enhanced binding affinity for ASGPR compared with monovalent GalNAc units, with affinity rankings in the order of tetraantennary > triantennary » biantennary » monoantennary. Studies by Biessen have suggested that a 2-nm interval between GalNAc and dendritic branch points may optimize NADs transportation efficacy. Additionally, hydrophobic linkers have been found to enhance GalNAc–ASGPR interactions.

48With the success of Alnylam in GalNAc, other companies have focused on RNA therapy and developed their delivery systems. Dicerna Pharmaceuticals has made considerable efforts to advance GalNAc delivery technology by adopting tetraantennary GalNAc conjugates (GalXC) for NADs delivery. In this conjugate, a unique four-ring structure is introduced on the passenger chain, enhancing the stability of the conjugate., Additionally, it accurately targets multiple GalXC ligands and successfully delivers siRNA to hepatocytes. Many candidates that involve this technology are currently undergoing clinical evaluation. Nedosiran, a siRNA targeting the silencing of lactate dehydrogenase A in hepatocytes (LDHA) with four covalently linked GalNAc, was approved by the FDA in 2023.

Exosomes

49Exosomes are vesicle-like structures with a diameter of 40–160 nm released after the fusion of intracellular multivesicular bodies (MVBs) with the cell membrane., As a bridge of intercellular communication, classical exosomes have a monolayer structure, which can encapsulate bioactive substances, such as proteins, lipids, DNA, and RNA, in the core and deliver them to effector cells to play specific biological functions (Fig. 4d).– They have been considered good candidates for NADs delivery.– For example, Kaban et al. used exosomes derived from natural killer (NK) cells as a carrier of siRNA targeting BCL-2 to treat patients with estrogen receptor-positive (ER + ) breast cancer, resulting in enhanced apoptosis of breast cancer cells. Additionally, another study used plasma exosomes to deliver siRNA to T cells and monocytes and caused post-transcriptional gene silencing in recipient cells. Furthermore, exosomes can easily cross biological barriers, such as the blood-brain barrier (BBB), which has good application potential in extra-hepatic-targeted NADs delivery.–

50When exosomes are used as NADs delivery vehicles, it is essential to consider the strategy of efficient drug loading. As a natural barrier of exosomes, the membrane structure of the lipid bilayer can protect NADs from external influences. Still, the existence of the membrane structure makes it difficult for exosomes to load drugs efficiently. The strategies of drug loading by exosomes are mainly divided into two categories.– The first is the exogenous route, in which the NADs are directly introduced into the obtained exosomes via electroporation, co-incubation, sonication, extrusion, and freeze-thaw cycling.– Although cargo uploading exogenously is simple and convenient to operate, the integrity of exosomes may be damaged during the loading process, which may affect the effect and require additional purification steps to remove the unloaded drugs., The other method is the endogenous pathway, which uses the endogenous pathway of exosome generation to indirectly improve the production of exosomes by promoting the expression of target nucleic acids and exosome secretion in productive cell lines. However, due to our lack of understanding of exosome biology, structure, and biogenesis, the strategy of endogenous drug loading still requires further research and optimization.

51One common disadvantage of exosomes is their random movement in vivo and lack of specific targeting., The abundant lipids and membrane-bound proteins on the surface of exosomes provide binding sites for targeting ligands, such as peptides, antibodies, and aptamers. These ligands can be stably attached to the surface of exosomes through covalent bonds to enhance their targeting ability. For example, Kim et al. modified exosomes with transferrin receptor-binding peptide (T7 peptide), which efficiently delivered AMO-21 into glioblastoma (GBM) cells in vitro. Furthermore, in vivo delivery results have shown that T7 peptide-modified exosomes effectively reduced the level of miR-21 in tumor cells and inhibited tumor growth compared with unmodified exosomes. Another study used a single-chain variable fragment (scFv) to modify exosomes derived from human umbilical cord blood mesenchymal stem cells (MSCs). In addition, exosomes can be genetically engineered to express ligands on their surfaces simultaneously. The most commonly used exosome surface protein is lysosome-associated membrane protein (LAMP). The N-terminus of LAMP-2B is located on the surface of exosomes and can specifically target given sequences.– After screening for cell-specific binding peptides for particular organs or tissues, such as the rabies virus glycoprotein peptide, LAMP-2B can be genetically modified to achieve targeted delivery (Fig. 4d).

52Thus far, approximately 40 companies worldwide, including Codiak Biosciences, Evox Therapeutics, Tavec Pharmaceuticals, Carmine Therapeutics, Anjarium, and Micromedmark Biotech, have developed exosome-based therapies, which are expected to provide cost-effective and more accurate targeted therapies in the clinic (https://bioinformant.com/companies-developing-exosome-technologies/). However, challenges, such as large-scale production, purity, and batch homogeneity of exosomes, still limit their clinical application. Additionally, there are no regulations for the control of therapeutic drugs based on exosomes that consider safety, effectiveness, and quality control, highlighting the urgent need for standardized methods and principles to manage these molecules.

Inorganic nanoparticles (INPs)

53INPs are nanocarriers based on inorganic substances that have attracted considerable attention due to their unique electrical and optical properties, biocompatibility, and low cytotoxicity. Commonly used INPs include gold nanoparticles (AuNPs), silica nanoparticles (SiNPs), magnetic nanoparticles (MNPs), and carbon nanotubes (CNTs) (Fig. 4e).– Unlike other delivery carriers, INPs possess a stable and robust structure, a large specific surface area, and tunable surface properties, allowing precise control of the drug delivery process through surface functionalization and controlled release modifications.

54AuNPs are widely developed INPs with excellent biocompatibility and low toxicity. Their flexible surfaces enable nucleic acids to bind to the gold nanoparticles directly., For example, Shrestha et al. developed a gold nanoparticle-mediated drug delivery platform for the co-delivery of doxorubicin and polo-like kinase 1 (Plk1) siRNA, offering an adaptable and straightforward platform for studying drug-siRNA combinations in cancer treatment. Notably, NU-0129, composed of siRNA targeting the GBM oncogene Bcl2Like12 (Bcl2L12) and a gold nanoparticle core, was the first spherical nucleic acid (SNA) drug administered systemically. The Phase 0 clinical study (NCT03020017) in eight patients with GBM showed that NU-0129 could pass through the BBB and accumulate in tumors, reducing the abundance of BCL2L12 protein and demonstrating its potential as an innovative therapy for GBM.

55MNPs are typically made of magnetic materials, such as iron oxide or iron platinum, and are usually coated with biocompatible materials to enhance their stability and biocompatibility. Under the influence of an external magnetic field, therapeutic drugs or molecules can be loaded onto magnetic nanoparticles and targeted to precise regions in the body., The unique superparamagnetic nature, lower toxicity, and site-specific targeting capabilities of MNPs make them excellent nanocarriers for NADs delivery.

56CNTs are cylindrical structures composed of a hexagonal arrangement of sp2 hybridized carbon atoms, also known as graphene. CNTs can be categorized into single-walled CNTs (SWCNTs) and multi-walled CNTs (MWCNTs). SWCNTs consist of a single layer of graphene sheets rolled seamlessly into a cylindrical tube. In contrast, MWCNTs are composed of multiple graphene layers wrapped around each other in a cylindrical shape. Although CNTs have poor solubility in both water and organic media, they can be chemically modified to improve their solubility, degradation ability, and drug-loading capacity while reducing toxicity. This simple surface functionalization has made CNTs promising carriers for NADs delivery in various diseases.

57Moreover, SiNPs are considered excellent carriers for NADs delivery. Research has shown that porous silicon nanoparticles (pSiNPs) can replace commonly used viral vectors or lipid transfection reagents as novel vectors for delivering siRNA to dendritic cells. Luo designed pSiNPs with ASO as targeted gene and drug delivery platforms for GBM treatment. These pSiNPs penetrate the BBB monolayer in vitro and target the brain after intravenous injection in an in situ GBM mouse model. This indicates that pSiNPs and their multifunctional strategies have strong potential for cancer treatment and gene delivery research.

Peptides

58Peptides comprise fewer than 100 amino acid residues, and they are between small molecules and proteins in size. Historically, peptides have been recognized for their diverse roles as hormones, signaling molecules, carriers, and supplements.– They are easily synthesized, possess relatively stable chemical properties, and exhibit a high selectivity. Due to their low immunogenicity and strong specific targeting capacity, peptides have emerged as promising carriers for selectively delivering NADs through various modalities (Fig. 4f)., Peptides exhibit multiple functions, including tissue targeting,– membrane penetration,– endosome escape,– and nuclear localization,– depending on their amino acid composition. Several peptides have been developed specifically for NADs delivery based on these unique properties for cell targeting, penetration, endosomal escape, and sub-organelle targeting (Fig. 5).,–

Targeting peptides

59Nonspecific cell binding is the leading cause of the off-target effects observed with several therapeutic molecules. The arginine-glycine-aspartic acid (RGD) sequence has been extensively applied in tumor-targeted therapy, mainly targeting αvβ3 receptors overexpressed on several tumor cells., A recent study demonstrated that siRNA conjugated to cyclic RGD (cRGD) could selectively enter cells that express αvβ3 integrin. Intravenously injected cRGD-siRNA molecules produced no innate immune response in mice with transplanted tumors. Additionally, researchers have found that incorporating siRNA into PEG-modified polylysine with cRGD can enhance gene silencing ability, improve cell uptake, inhibit glioma angiogenesis, and delay tumor progression after systemic administration in mice.

60The acidic extracellular microenvironment has become an effective disease diagnosis and treatment target. pH low insertion peptides (pHLIPs), derived from the C-helix of bacteriorhodopsin, can sense the pH value near the plasma membrane and deliver drugs to pathological tissues. In acidic environments, the elevated proton concentration increases the hydrophobicity of peptides. pHLIPs spontaneously fold to form α helices, which insert and cross the cell membrane to transport conjugated NADs into cells., In anti-tumor therapy, it has been demonstrated that pHLIPs can deliver PNAs to cancer cells due to their natural targeting abilities., For example, in a mouse model of lung adenocarcinoma, the delivery of PNAs targeting CEACAM6 using pHLIPs resulted in CEACAM6 gene silencing and tumor growth inhibition.

Cell-penetrating peptides (CPPs)

61CPPs are a short peptide class consisting of 5–30 amino acids that can cross the cell membrane directly. They can penetrate the cell membrane by themselves and effectively enhance the intracellular delivery of NADs, aiding their interaction with the target to achieve therapeutic goals.–

62Despite their significant therapeutic potential, CPPs have some limitations. One major issue is their lack of selectivity, as they can carry NADs into almost all cell types. To address this, researchers have developed strategies such as local administration, targeting ligands on CPPs, or using activatable CPPs that penetrate only under specific biological stimuli., Ensuring the stability and biological activity of CPPs during the delivery process is also a challenge. Modifications can be made to the termini of existing CPPs or the peptide backbone can be adjusted, such as through peptide cyclization, to improve stability and cell permeability., Another limitation of CPPs is their limited clinical efficacy, often requiring high concentrations and doses to achieve a therapeutic effect, which can cause significant toxicity and side effects, hindering the development of clinical applications. Current research has found that inducing peptides to form multimers and using multifunctional fusion peptides can improve the delivery efficiency of CPPs to some extent.–

Endosomal escape peptides

63Endosomal escape is a significant challenge for non-viral NADs delivery systems. Typically, after arriving at a specific cell, NADs pass through the cell membrane and reach the cytoplasm through various mechanisms, such as direct penetration or endocytic uptake., However, peptide carriers and their cargos often become trapped in acidified endosomes, preventing their entry into the cytoplasm, nucleus, and other subcellular compartments.,

64Fusogenic peptides are short peptides that promote endosomal release by enhancing interactions with endosomal membranes., In a low pH environment, fusogenic peptides undergo pH-dependent conformational changes to form α-helices, which insert into the endosomal membrane, causing instability and decomposition of the membrane structure. This allows internalized NADs to dissociate from the fusogenic peptide delivery system and escape into the cytoplasm to exert their therapeutic effects. Many fusiform peptides of viral and non-viral origin, such as the INF7 family, L17E family, GALA/KALA family,– and HA family, can disrupt endosomal membranes and increase cytoplasmic delivery. One study evaluated the ability of the H5WYG peptide to deliver NADs and promote endosomal release, confirming the elevated endosomal escape function of this clostridial peptide. Many studies have shown that self-assembled peptide carriers modified with fusogenic peptides can overcome intracellular delivery obstacles., For instance, the fusogenic peptide L17E was linked to peptide self-assembled disks using click chemistry. Compared with unmodified disks carrying plasmid DNA, nanodisks modified with L17E demonstrated enhanced endosomal escape and improved transfection efficiency in cell culture.

Peptide-targeting subcellular organelles

65The structural integrity and functional stability of organelles are essential for maintaining normal cellular physiological functions. Dysfunction of these organelles can lead to various diseases, including diabetes, neurodegenerative diseases, CVDs, and cancer, making them potential therapeutic targets.– As mentioned earlier, the efficacy of NADs therapy largely depends on the efficient and safe delivery of NADs to their specific action sites within the body. After escaping from endosomes, the next challenge is transporting NADs quickly and effectively to the nucleus or specific organelles. Peptide targeting of subcellular organelles offers a promising strategy to guide NADs to dysfunctional organelles, thus achieving optimal therapeutic effects. This approach provides a potential method to overcome the intracellular delivery obstacles and enhance the efficacy of NAD-based therapies.

Multifunctional peptides

66In previous clinical trials, using individual functional peptides for NADs delivery showed limited efficacy due to their inability to overcome various delivery obstacles. To address this issue, researchers have integrated different peptides or functional domains capable of overcoming transfer barriers into a single peptide-based carrier to enhance delivery efficiency.– Compared with individual functional peptides, multifunctional peptide carriers considerably improve transfection efficiency and have demonstrated outstanding potential in clinical applications.– For example, amino acid pairing (AAP) peptides are a novel class of self-assembled biomolecules comprising two main structural domains: an amino acid pairing domain and a cell permeability domain. AAP peptides possess recognition and membrane-targeting functions, facilitating gene delivery through interactions with DNA and siRNA.

67The discovery of peptide-based NADs delivery systems is accelerating by the use of various peptide combinations and high-throughput screening, providing new directions for optimizing and developing peptide carriers.– For example, Li et al. designed a multifunctional peptide vector (PLD-R9-G-NLSW) containing the CPP R9, NLS, and 2,3-dimethylmaleic anhydride-modified PLL. This vector condenses with the pIRES-VEGF plasmid to form a complex for gene delivery. In vitro results showed that the complex considerably improved gene internalization and transfection efficiency while reducing cytotoxicity. However, researchers have discovered that the immediate coupling of individual peptides can affect the function and activity of the units. Given the likelihood that distinct peptides may interact with each other during the fusion process, the final functional characteristics of the peptides may not involve a simple integration., This phenomenon suggests that the interaction mechanism between combined peptides and the structure-activity relationship needs to be explored in more detail.

68Recently, peptides have been applied as ligands to achieve delivery functions in complexes known as peptide-oligonucleotide conjugates (POCs)., In this approach, oligonucleotides or their analogs are covalently linked to one or more peptide residues to form POCs. Various methods, including disulfide bonds, thioether bonds, thiol-maleimide bonds, phosphodiester bonds, and click chemistry, are used for this covalent connection.– The primary advantage of covalent conjugation is that the resulting product is a single compound with defined structural and stoichiometric characteristics, aligning with the ideal properties for drug design and in vivo application., However, covalent conjugation also has drawbacks. Interactions between cationic peptides and negatively charged oligonucleotides can enhance toxicity, affect pharmacokinetic and pharmacological properties, and limit the efficacy of these therapies. Additionally, the interaction between anions and cations can complicate large-scale preparation and purification of these conjugates.

69The most advanced application of POCs is the delivery of charge-neutral oligonucleotides, such as PNA and PMO, using CPPs.– CPP-PNA conjugates with Tat and R8 have been successfully applied to PNA delivery, and showed sound therapeutic prospects in anti-virus, antibacterial, and anti-inflammatory therapy. Beyond CPPs, other functional peptides have also been exploited for PNA delivery. For instance, Soudah et al. used a conjugate of the cytoplasmically localized internalized peptide (CLIP6) and PNA to treat GBM cells, considerably upregulating the tumor suppressor Mnk2a and promoting cancer cell death. Kaplan et al. showed that pHLIP-αKu80 (γ), which was created by covalently conjugating pHLIPs with PNA targeting KU80 via disulfide bonds, could selectively reduce Ku80 expression under acidic conditions. In mice, intravenous injection of fluorescently labeled pHLIP-αKu80 (γ) targeted tumors and reduced Ku80 expression.

70The development of peptide-phosphoryl diamine morpholino oligonucleotide (PPMO) conjugates has further advanced NADs delivery, particularly for neuromuscular diseases, such as spinal muscular atrophy (SMA) and DMD., A recent study demonstrated that subcutaneous injection of a CPP-DG9 and PMO conjugate improved muscle strength and innervation in mice with severe SMA, significantly extending their median survival with no apparent side effects. To enhance the delivery of neutrally charged oligonucleotides, Gait and Wood developed a series of arginine-rich CPPs named [PNA/PMO]-internalized peptides (Pip), including Pip2a, Pip2b, Pip5e, and Pip6a. Studies have shown that Pip6a-PMO effectively rescues the disease phenotype and improves the survival rate of severe SMA mice, showing strong efficacy in the central nervous system and peripheral tissues., Pip6a-PMO predicts a potent therapeutic option that combines the genetic precision of SSO with the systemic delivery efficacy of peptides.

71With technological advances, various novel POCs have demonstrated the feasibility of delivering siRNA, ASO, and miRNA in vitro., Studies have found that bivalent cRGD successfully transports VEGF receptor 2 (VEGFR2)-siRNA into tumor cells in a mouse non-small cell lung cancer xenograft model, downregulating VEGFR2 expression and significantly inhibiting cancer progression. Kim et al. designed a dual-targeting drug delivery system for miR-21 inhibitors, consisting of a PDL1-binding peptide covalently linked with an anti-miR-21 inhibitor via a click reaction. Pep-21 treatment specifically silenced target miR-21 in B16 melanoma cells and M2 macrophages, reducing tumor cell migration and inhibiting tumor progression. PepGen developed a POC drug, PGN-EDO51, using its enhanced delivery oligonucleotide platform, which skips exon 51 in the DMD gene. In Phase I clinical trials, PGN-EDO51 showed good safety, tolerability, and efficacy, and Phase II trials are ongoing.

72Electrostatic or hydrophobic interactions between peptides and NADs create self-assembling peptide-based nanoparticles.– These complexes protect nucleic acids from nuclease degradation and reduce the likelihood of adverse reactions. Using this strategy, Ryu et al. developed an S-R11 fusion peptide (space peptide bound to polyarginine) that forms stable nanocomposites with siRNA molecules through electrostatic attraction and hydrogen bonding, facilitating siRNA delivery to difficult-to-transfect immune cells. Sirnaomics’ histidine-lysine copolymer peptide nanoparticle (PNP) delivery platform has demonstrated clinical therapeutic potential for RNAi therapy. In contrast, non-covalent strategies have been used for delivering siRNA, plasmid DNA, and splicing correction oligonucleotides., The peptide p5RHH has been efficiently used to transfect siRNA and mRNA into human cartilage to reduce chondrocyte apoptosis and prevent cartilage degeneration– as well as into cardiac tissue for treating abdominal aortic aneurysm to reduce the risk of aortic rupture and sudden death in mice.

Clinical applications of NADs

73Theoretically, NADs can cure any disease by allowing the selection of the correct nucleotide sequence on the target gene. Unlike conventional therapeutics, NADs induce long-lasting or curative effects due to their distinct physicochemical and biological properties. Numerous NADs have transitioned from bench to bedside and have successfully been approved for clinical trials (Fig. 6). Several NADs, including ASOs, aptamers, siRNAs, and mRNA vaccines, have been adopted as vaccines for treating rare genetic diseases, cancer, ophthalmic diseases, CVDs, and infections. Table 2 summarizes NADs successfully applied in clinical experiments for treating human diseases.

Rare genetic diseases

74Transthyretin amyloidosis (ATTR) is a rare systemic disease characterized by the progressive deposition of misfolded TTR protein in the heart and peripheral nerves, leading to transthyretin amyloid polyneuropathy (ATTR-PN) and transthyretin amyloid cardiomyopathy (ATTR-CM)., Several NADs have been approved for ATTR treatment, including ASOs, such as inotersen, and eplontersen, as well as siRNAs, such as patisiran and vutrisiran. These therapies work by disrupting the relevant mRNA, thus inhibiting TTR synthesis. Additionally, researchers are exploring new methods to block TTR production via gene-editing techniques. For instance, a Phase III clinical trial evaluated the efficacy and safety of NTLA-2001, a CRISPR-Cas9-based therapy, in participants with ATTR-CM. In a previous Phase I trial, six patients treated with a single dose of NTLA-2001 showed significant reductions in serum TTR protein levels, with no serious adverse effects or liver damage reported.

75DMD is a rare genetic muscle disorder caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein. Patients typically exhibit symmetric, progressive muscle weakness and atrophy, ultimately leading to premature death due to respiratory and cardiovascular complications. Significant progress has been made in DMD therapeutic strategies, including NADs. Approved ASO drugs target exon 45 (casimersen),, exon 51 (eteplirsen),, and exon 53 (golodirsen and viltolarsen), to induce specific exon skipping in the dystrophin gene, thus delaying disease progression. Researchers have developed second-generation skipping drugs, called PPMOs, to enhance targeting and skipping activity. Sarepta’s SRP-5051, an ASO conjugated with a targeting peptide, has shown higher levels of dystrophin expression and exon skipping rates than eteplirsen. This drug is currently in Phase II clinical trials (NCT04004065). Additionally, PepGen’s PGN-EDO51, designed to skip exon 51 in the DMD gene, has shown promising results in Phase I clinical trials and is now in Phase II (NCT06079736).

76Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the dysfunction of upper and lower motor neurons. Approximately 10% of ALS cases are familial ALS, with various disease-causing genes identified, including superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9ORF72), and fused in sarcoma (FUS)., The first NAD approved for ALS was tofersen (Qalsody®), a PS 2’-MOE ASO targeting SOD1 mutations., Ulefnersen (ION-363), an antisense therapy targeting the FUS gene, is currently in Phase III trials for FUS-ALS. However, clinical trials for C9ORF72-targeted therapies WVE-004 and Tadnersen (IONIS-BIIB5Rx) have been terminated due to poor efficacy.

77Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by defects in hepatic glycoxidation metabolism, leading to excessive endogenous oxalate production. It is characterized by recurrent urinary calculi, nephrocalcinosis, and progressive renal damage. PH1 is associated with a deficiency or functional defect in alanine glyoxylate aminotransferase., Lumasiran, a siRNA drug that targets hydroxy acid oxidase 1 to reduce hepatic oxalate production, was the first drug approved for PH1. Nedosiran, another RNAi drug developed by Dicerna Pharmaceuticals that targets LDHA, is currently being evaluated for its efficacy in reducing oxalate production.

78SMA is a genetic neuromuscular disease caused by the deletion or mutation of the survival motor neuron 1 (SMN1) gene, leading to the loss of alpha motor neurons and progressive muscle atrophy. The SMN2 gene, highly similar to SMN1, produces mostly non-functional SMN protein due to differences in exon 7 splicing., Correcting exon 7 splicing in SMN2 can compensate for the lack of SMN1, producing functional SMN protein and improving symptoms., Nusinersen, a modified ASO targeting the intronic splicing silencer N1 of the SMN2 gene, promotes the production of the full-length SMN protein. Several clinical trials have confirmed the efficacy and safety of nusinersen, leading to better motor milestone responses and higher event-free survival rates.–

Cancer

79The occurrence and progression of cancer are closely tied to the activation of oncogenes and the loss of tumor suppressor genes. NADs, which target specific genes, offer new methods for cancer treatment. For example, transforming growth factor beta 1 (TGFβ1), a multifunctional cytokine, can alter the tumor microenvironment when dysregulated, promoting angiogenesis and immune suppression, thus influencing tumor progression., Therefore, blocking TGF-β signal transduction is a critical strategy in cancer treatment.

80Cotsiranib is a siRNA therapy developed by Sirnaomics that uses the PNP delivery platform, containing two active siRNAs targeting TGFβ1 and cytochrome C oxidase subunit 2 mRNA. A Phase II clinical trial (NCT04669808) for the in situ treatment of basal cell carcinoma showed a positive therapeutic effect and achieved 100% complete clearance. Another anticancer candidate, STP707, is currently being evaluated in a Phase I trial (NCT05037149) for safety, tolerability, and anti-tumor activity in participants with advanced/metastatic or surgically unresectable solid tumors.

81In addition, tumor vaccines carrying NADs are considered feasible therapeutic approaches for most solid tumors. IGV-001 is a vaccine targeting GBM, designed based on the Imvax platform Goldspire™. Unlike traditional tumor vaccines, IGV-001 is prepared by mixing tumor tissue removed from the patient’s brain with an insulin-like growth factor 1 receptor antisense oligonucleotide (IMV-001), which inhibits tumor growth. Then, this mixture is encapsulated in biodiffusion chambers with a 0.1-μm pore size, allowing large molecules to permeate and be implanted into the patient’s abdomen. This aims to induce a tumor-specific immune response. In earlier clinical trials, IGV-001 demonstrated good tolerance and safety (NCT02507583). Imvax is conducting a randomized, multicenter, double-blind, placebo-controlled Phase IIb study (NCT04485949) to evaluate IGV-001 in patients with newly diagnosed GBM. Additionally, personalized mRNA neoantigen vaccines, such as mRNA-4157, encode multiple antigens to stimulate a patient-specific immune response. Clinical trials are underway for melanoma, non-small cell lung cancer, and other solid tumors. A Phase IIb trial of mRNA-4157 in combination with pembrolizumab for patients with resected high-risk melanoma showed that this combination therapy prolonged recurrence-free survival compared with pembrolizumab monotherapy and had a manageable safety profile. Combination therapies for melanoma and non-small cell lung cancer have entered Phase III clinical trials (NCT05933577 and NCT06077760). This is expected to be the first mRNA tumor vaccine on the market.

Ophthalmic diseases

82AMD is a complex eye disease primarily categorized into dry and wet/neovascular AMD. Aptamers have shown promise in AMD treatment. Pegaptanib, a VEGF antagonist with a three-dimensionally structured aptamer, was initially used to inhibit pathological neovascularization and reverse disease progression but was later removed from the market. RBM-007, an RNA aptamer designed to target fibroblast growth factor 2 (FGF2), is currently in Phase II clinical trials for treating neovascular AMD (nAMD)., FGF2 promotes angiogenesis and retinal fibrosis by stimulating vascular endothelial cell proliferation and inducing VEGF secretion. Unlike traditional anti-angiogenic therapies that target VEGF, Sylentis developed SYL1801, an siRNA targeting NOTCH Regulated Ankyrin Repeat Protein (NRARP), to prevent and control nAMD progression. SYL1801 is administered as eye drops rather than via intravitreal injection, downregulating NRARP expression and inhibiting retinal neovascularization. Clinical trials testing various doses of SYL1801 eye drops in healthy volunteers showed good safety and tolerability. Four of the 36 patients tested experienced mild adverse events such as blepharitis, keratitis, hyperemia, and ocular irritation, all of which resolved within 72 h. Currently, the drug is in Phase II clinical recruitment to compare the safety and efficacy of three different doses in patients with nAMD (NCT05637255).

83Dry eye disease (DED) is a common ocular condition characterized by tear film alterations, ocular inflammation, and neurosensory abnormalities.– Tivanisiran (SYL1001), an unmodified siRNA eye drop developed by Sylentis, targets the transient receptor potential vanilloid 1 mRNA to alleviate ocular discomfort and pain. It has improved the quality of eye redness and tear film in human and animal models. It is undergoing Phase III trials to evaluate its safety in treating DED caused by dry eye syndrome (NCT05310422 and NCT04819269).

84QR-110, an ASO drug in Phase III trials, was designed to address Leber congenital amaurosis type 10 caused by the p.Cys998X mutation in the centrosomal protein 290 gene. QR-110 binds to pre-mRNA, restoring proper splicing and producing fully functional proteins. Another candidate, ultevursen (QR-421a), is an ASO therapy for treating vision loss in patients with pigmentary retinopathy due to mutations in exon 13 of the USH2A gene. This drug aims to halt or reverse vision loss by restoring the function of the usherin protein through exon skipping in Usher syndrome type 2a and non-syndromic retinitis pigmentosa.

CVDs

85CVDs remain a leading cause of mortality worldwide and pose a severe public health challenge. These diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, and heart failure, are closely linked to genetic, metabolic, and environmental factors. Researchers continually explore new disease targets and develop precision-targeted NADs to address CVDs. Advancements in nucleic acid chemistry have considerably improved drug stability and pharmacokinetics, offering more effective long-term treatment options for reducing the incidence and mortality of CVDs.

86Genetic, epidemiological, and clinical research has indicated that lipid abnormalities, such as in low-density lipoprotein cholesterol (LDL-C), are critical factors in the occurrence and progression of CVDs., Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an essential regulator of LDL-C metabolism. By reducing the number of LDL receptors (LDLR) on the surface of liver cells, PCSK9 leads to the accumulation of LDL-C, increasing the risk of CVDs., NADs targeting PCSK9 work by blocking the synthesis of PCSK9 protein and preventing LDLR degradation, thus promoting LDL-C absorption and reducing its levels in the bloodstream. Inclisiran, the world’s first siRNA drug for CVDs, is administered via subcutaneous injection and conjugated with N-acetyl galactosamine to enhance its targeted uptake by liver cells. Results from several Phase III clinical trials (ORION-9/10/11, NCT03397121, NCT03399370, and NCT03400800) have shown that subcutaneous injections of inclisiran every 6 months considerably reduce LDL-C levels by 48–52%, demonstrating sustained efficacy and good tolerability. Injection site reactions were more common in the inclisiran group but were generally mild and not persistent (5.0% vs. 0.7%)., Inclisiran has been approved for treating various cardiovascular conditions, including atherosclerotic cardiovascular disease (ASCVD), primary hypercholesterolemia, mixed dyslipidemia, and heterozygous familial hypercholesterolemia (HeFH).

87Lipoprotein(a) [Lp(a)] is a cholesterol-rich LDL-like particle formed by the covalent bonding of apolipoprotein(a) [Apo(a)] and Apo B100 via disulfide bonds. Elevated Lp(a) levels are considered independent risk factors for ASCVD, heart failure, and aortic valve stenosis.– Although no targeted drug for reducing Lp(a) levels has been approved thus far, several candidates have shown promise in clinical trials. For example, pelacarsen, an Lp(a) ASO drug developed by Ionis in collaboration with Novartis AG, effectively lowers Lp(a) levels by selectively cleaving Apo(a) gene (LPA) mRNA. In a Phase II trial, pelacarsen reduced Lp(a) levels by 35–58% depending on the dose, with no significant differences in safety indicators compared with the placebo. The Phase III trial Lp(a)-HORIZON is underway, involving 8,323 patients with established ASCVD, and is expected to be completed in 2025 (NCT04023552). In addition to ASO drugs, siRNA therapies offer unique solutions for CVDs. Olpasiran and lepodisiran are GalNAc conjugates containing siRNAs that target the LPA gene, promoting RISC-mediated degradation of Apo(a) mRNA and preventing Lp(a) particle assembly in hepatocytes., Olpasiran demonstrated a dose-dependent reduction in Lp(a) levels, with a single dose of 9 mg or higher reducing Lp(a) concentrations by over 90% for several months (NCT03626662). Phase II trials of olpasiran [OCEAN(a)-DOSE] (NCT04270760) showed that a higher dose (75 or 225 mg) could reduce the Lp(a) level of patients by more than 95% compared with the placebo. Regarding safety, the overall incidence of AEs was similar between the dose and placebo groups. Among them, the most common AE of olpasiran was injection site reaction (primarily pain). The Phase III trial of olpasiran aims to compare its effects with the placebo on the risk of coronary heart disease death, myocardial infarction, and urgent coronary revascularization in ASCVD patients with elevated Lp(a), with results expected by 2026 (NCT05581303). Similarly, lepodisiran has shown well-tolerated and dose-dependent reductions in serum Lp(a) concentrations, with a Phase III trial currently recruiting participants and expected to be completed by 2029 (NCT06292013 and NCT04914546).

88Beyond lipid-lowering therapies, there are positive developments in other areas of NADs application. Zilebesiran (ALN-AGT01), which targets angiotensinogen (AGT), is being developed for hypertension treatment. It suppresses the generation of angiotensin I and II, inhibiting the renin-angiotensin-aldosterone system to reduce blood pressure. Phase I studies showed that a single subcutaneous dose of zilebesiran of 200 mg or more considerably decreased serum AGT levels and 24 h ambulatory blood pressure for up to 24 weeks, with only mild injection site reactions observed. In Phase II trials (KARDIA-1), zilebesiran reduced systolic blood pressure in all treated patients, with effects lasting 6 months, opening new possibilities for NADs use in treating hypertension and CVDs.

Infectious diseases

89The COVID-19 pandemic, caused by the severe acute respiratory SARS-CoV-2, has considerably advanced the development of mRNA vaccines. These candidate vaccines are LNP-encapsulated mRNA-based formulations that encode the full-length SARS-CoV-2 spike protein and its receptor-binding domain. They induce an immune response again st the spike protein on the virus’s surface, blocking its entry into cells and providing an antiviral effect., mRNA-1273 was one of the first COVID-19 vaccines to enter clinical trials, taking only 42 days from the publication of the virus’s genetic sequence to the production of the first batch of samples. The final analysis from its Phase III clinical trials showed a 94.1% efficacy in preventing COVID-19 illness and a 100% efficacy in preventing severe COVID-19. Similarly, BioNTech’s mRNA vaccine BNT162b2 demonstrated a 95% efficacy against COVID-19, with protection rates of over 94% for individuals aged 65 and older. These vaccines were designed, manufactured, evaluated, and brought to market in an extremely short period compared with traditional vaccine development timelines, highlighting the unique advantages of mRNA vaccines, including high safety, simple design, broad target range, and ease of scaling up production.

90Chronic hepatitis B, caused by hepatitis B virus (HBV) infection, is a significant global public health problem. Current clinical treatment guidelines aim for a functional cure for CHB, which involves sustained negativity for hepatitis B surface antigen (HBsAg), undetectable HBV DNA, normal liver biochemical indicators, and improvement of liver tissue lesions after treatment cessation. Despite the efficacy of existing drugs, achieving a functional cure remains challenging. Bepirovirsen, developed by GlaxoSmithKline (GSK), is a 2’-MOE-modified ASO that targets all HBV RNAs, promoting RNase H-mediated RNA degradation, reducing HBV replication, and inhibiting HBsAg production. Additionally, bepirovirsen has immunostimulatory activity through Toll-like receptor 8, potentially helping the immune system permanently clear the virus from the bloodstream. Data from a Phase IIb clinical trial indicated that after 24 weeks of treatment, bepirovirsen can reduce levels of HBsAg and HBV DNA. Furthermore, another Phase II trial (B-Sure) evaluated the durability of bepirovirsen’s antiviral effect (NCT04954859). Recruitment for Phase III clinical trials to assess the efficacy and safety of bepirovirsen is also underway, with results expected in early 2026 (NCT05630807 and NCT05630820). Several candidate siRNA drugs, including GSK-5637608 (JNJ-73763989, GSK), VIR-2218 (ALN-HBV02, Alnylam & Brii Biosciences Ltd. & Vir Biotechnology), and imdusiran (ARB-270729, Arbutus Biopharma), have entered Phase II clinical trials, demonstrating a strong ability to reduce HBsAg levels. In practical clinical applications, these siRNA therapies often form combination treatments with nucleoside analogs, TLR agonists, or peginterferon, considerably enhancing the possibility of a functional cure for HBV. For example, VIR-2218, a GalNAc-siRNA conjugate that targets HBV, uses enhanced stability chemistry plus technology to stabilize the siRNA in vivo and reduce off-target effects. Currently, combination therapies involving VIR-2218 are in multiple Phase II trials for HBV patients, and results are eagerly awaited (NCT04856085 and NCT04412863).

Future perspectives of NADs development

91Although many NADs have shown promising preclinical results, the number of NADs approved by the FDA for clinical use remains limited. The complexity of nucleic acids and their types, sizes, and mechanisms of action have made the development of NADs systematically very complex. For successful NADs design, critical factors must be considered regarding sequence design, modification, and delivery, as well as the clinical translation, medical indication, and scale production feasibility.

Sequence design of NADs

92Typically, NADs are designed and screened based on the pathogenic genes of specific diseases. By leveraging existing sequence design and screening techniques, AI-assisted designs have accelerated the design and screening process, making it more accurate, and have been adapted to the needs of personalized therapy., Furthermore, patenting key modification sites in the selected target sequences is crucial to maintaining a competitive advantage.

Structure modification and delivery system

93Considering the inherent physicochemical properties of NADs, the critical issue for their application is whether they can reach the target site and exert the expected therapeutic effects. Much evidence supports that it is unrealistic to address all drug delivery issues through a single modification method or a “universal” delivery vector. NADs should exhibit good stability to withstand nucleases and immune system clearance to achieve sound therapeutic effects. In addition to being delivered explicitly to the required tissues, they must reach the targeted cells, efficiently released into the cytoplasm, and exhibit in vivo biocompatibility. Initially, choosing appropriate strategies for the design of NADs is necessary based on the disease type and the required functional nucleic acid. For example, from the approved NADs, ASO drugs often do not require carriers for efficient delivery and only require appropriate modifications, such as PS and 2’ position modifications. Small NADs, such as siRNA, and large ones, such as mRNA, in addition to the necessary modifications, still require the aid of delivery vectors. siRNA typically uses nucleic acid conjugations for delivery, while mRNAs often rely on LNPs for compression and encapsulation. Furthermore, understanding the structure-activity relationship between nucleic acids and the delivery vector and different interactions (hydrophobic, electrostatic, and covalent interactions) and their effect on drug stability is crucial for developing stable and effective NADs. NADs interact with various environments during delivery, and individual chemical modifications or delivery carriers may not suffice to overcome physiological barriers. Combining nucleic acid chemical modifications with drug delivery systems is promising for better therapeutic outcomes. Moreover, researchers are developing various combined carrier-use modes to facilitate effective drug loading, precise targeting, and release. The emergence of intelligent, responsive nanocarriers may help NADs interact with complex environmental changes, responding to specific in vivo changes, such as pH, redox conditions, or external stimuli (ultrasound, light, magnetic fields, and electric fields). These carriers can improve transfection efficiency in target cells and reduce toxic side effects on normal tissues and cells., However, hybridizing multiple carriers and modifying functional ligand molecules increase the technical difficulties and manufacturing costs.

Safety

94A serious issue in developing these therapeutics is in vivo safety. Despite the detailed understanding of the physicochemical properties of NADs, the potential immunogenicity and toxicity of carriers and related modifications may pose additional challenges to safe and effective NADs delivery., For example, early application of relatively mature PPMO technology showed that high doses of CPP-PMO conjugates caused kidney injury in rats. Cationic polymers, such as PLL/PEI,, have induced cell apoptosis and inflammation in vivo.

Pharmacokinetic properties and adverse reactions

95Advanced technologies have generated NADs complexes with different properties. Their chemical structure, dosage form, and administration route are the main determinants of their absorption, distribution, metabolism, and excretion, thereby affecting their efficacy and safety., For example, based on the unique mechanism of action of ASOs, the main safety issues are severe hepatotoxicity and nephrotoxicity caused by drug accumulation. Therefore, evaluating NADs delivery systems’ drug metabolism and pharmacokinetics is essential for clinical development. Various bioanalytical methods, such as chromatographic techniques for determining drug plasma concentrations and metabolism, and imaging technology for estimating drug distribution, are used, although each has limitations. Low sensitivity and poor discrimination affect the accuracy of determination results, highlighting the importance of developing novel analytical methods. Although previous studies have used nano-fluorescent probes to detect the cellular delivery efficiency of oligonucleotide molecules,,, more pharmacokinetic data on biodistribution, immune compatibility, and toxicity are needed for clinical translation and practical therapeutic application of these systems.,

Pathological indications

96Most diseases exhibit variability in their phenotypes, making it difficult to achieve a curative effect by targeting a single gene. Issues, such as a small patient population and unique targets, often result in a lack of attention from pharmaceutical companies. Therefore, analyzing the pathogenesis of diseases at the genetic level and developing a personalized treatment plan may offer the possibility of a permanent cure for rare and currently incurable genetic diseases. Compared with antibody drugs and small molecule drugs, NADs are specifically favorable for personalized therapies owing to their strong specificity for diverse targets. They have been explored in the development of new therapies for various diseases. Thus far, genetic diseases have been the most approved indication category for NADs. Additionally, breakthroughs in gene therapy and gene-cell combined therapy are promising for the large-scale clinical application of NADs. For instance, Casgevy®, based on the CRISPR/Cas9 gene-editing system, was the first successful attempt at disease treatment, promising a “one-time treatment for a lifelong effect.” However, the complexity of clinical applications and the difficulty of target selection in gene editing have led to long treatment cycles and high costs. Moreover, the application range of NADs is gradually expanding from rare diseases to common diseases such as chronic diseases, infectious diseases, and ophthalmic diseases. The development of curative drugs for indications with large patient populations, such as potential cures for hepatitis B, may address broader clinical needs.

Scale production

97Like other drugs, the production of NADs involves multiple technical stages, including raw material collection, synthesis, separation, purification, transportation, and storage, requiring large-scale production capabilities and stringent quality control. Additionally, the specific requirements for sequence size, purity, and modification and delivery methods of NADs, based on different research needs, increase the demands on the production model. Therefore, to achieve large-scale clinical application, NADs must ensure easy production, quality control, and transportation. Moreover, as regulatory policies become more refined and the industry chain further develops, companies should seek collaboration opportunities while increasing research and development investments. Collaborations between internationally renowned enterprises in terms of sharing advanced technology and management experience can enhance research and development capabilities and production capacity.

98In summary, the development of NADs has undergone a long process, with research on the mechanisms of action of different types of drugs and breakthroughs in chemical modification and delivery technologies. These have transformed NADs from conceptual to practical clinical treatment tools. However, some clinical promotion and application shortcomings still require further development. The organic combination of specific therapeutic nucleic acid molecules, targeted modifications, and functionalized delivery carriers may become vital to achieving personalized nucleic acid therapy and addressing unmet clinical needs.

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67.
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MicroRNA: trends in clinical trials of cancer diagnosis and therapy strategies · 2023
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On measuring miRNAs after transient transfection of mimics or antisense inhibitors. · 2013
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RNAa Is Conserved in Mammalian Cells · 2010
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Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics · 2023
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196.
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mRNA vaccines for cancer immunotherapy · 2022
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247.
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248.
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250.
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Pantazopoulou VI, et al. From the argonauts mythological sailors to the argonautes RNA-silencing navigators: their emerging roles in human-cell pathologies. Int. J. Mol. Sci. 2020;21:4007.
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Choung S, et al. Chemical modification of siRNAs to improve serum stability without loss of efficacy. Biochem. Biophys. Res. Commun. 2006;342:919-927.
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255.
Delivery of oligonucleotide‐based therapeutics: challenges and opportunities · 2021
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256.
Chen C, Yang Z, Tang X. Chemical modifications of nucleic acid drugs and their delivery systems for gene-based therapy. Med. Res. Rev. 2018;38:829-869.
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258.
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259.
Potential applications of peptide nucleic acid in biomedical domain · 2020
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260.
Chen W, Dong B, Liu W, Liu Z. Recent advances in peptide nucleic acids as antibacterial agents. Curr. Med. Chem. 2021;28:1104-1125.
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261.
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262.
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263.
Dhillon S. Viltolarsen: first approval. Drugs. 2020;80:1027-1031.
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264.
Shirley M. Casimersen: first approval. Drugs. 2021;81:875-879.
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265.
Egli M, Manoharan M. Chemistry, structure and function of approved oligonucleotide therapeutics. Nucleic Acids Res. 2023;51:2529-2573.
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267.
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269.
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270.
Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of in vivo imaging · 2022
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271.
Hald Albertsen C, et al. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv. Drug Deliv. Rev. 2022;188:114416.
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272.
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273.
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274.
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275.
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276.
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277.
Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo** · 2012
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278.
Ferraresso F, et al. Comparison of DLin-MC3-DMA and ALC-0315 for siRNA delivery to hepatocytes and hepatic stellate cells. Mol. Pharmaceutics. 2022;19:2175-2182.
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279.
Zhang M, Sun J, Li M, Jin X. Modified mRNA-LNP vaccines confer protection against experimental DENV-2 infection in mice. Mol. Ther. Methods Clin. Dev. 2020;18:702-712.
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280.
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281.
An ionizable lipid toolbox for RNA delivery · 2021
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282.
Mui BL, et al. Influence of polyethylene glycol lipid desorption rates on pharmacokinetics and pharmacodynamics of siRNA lipid nanoparticles. Mol. Ther. Nucl. Acids. 2013;2:e139.
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283.
Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver · 2020
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284.
Song LY, et al. Characterization of the inhibitory effect of PEG-lipid conjugates on the intracellular delivery of plasmid and antisense DNA mediated by cationic lipid liposomes. Biochim. Biophys. Acta. 2002;1558:1-13.
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285.
Kong L, Campbell F, Kros A. DePEGylation strategies to increase cancer nanomedicine efficacy. Nanoscale Horiz. 2019;4:378-387.
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286.
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287.
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288.
Kim J, Eygeris Y, Gupta M, Sahay G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 2021;170:83-112.
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289.
Liu S, et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing. Nat. Mater. 2021;20:701-710.
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290.
Paunovska K, et al. Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses. Adv. Mater. 2019;31:e1807748.
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291.
Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles · 2021
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292.
Cheng Q, et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat. Nanotechnol. 2020;15:313-320.
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293.
mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications · 2023
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294.
Low immunogenicity of LNP allows repeated administrations of CRISPR-Cas9 mRNA into skeletal muscle in mice · 2021
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295.
A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus · 2021
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296.
Kotit S. Lessons from the first-in-human in vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 trial in patients with transthyretin amyloidosis with cardiomyopathy. Glob. Cardiol. Sci. Pract. 2023;2023:e202304.
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297.
Effect of mRNA-LNP components of two globally-marketed COVID-19 vaccines on efficacy and stability · 2023
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298.
Polymeric Nanoparticles in Gene Therapy: New Avenues of Design and Optimization for Delivery Applications · 2019
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299.
Patnaik S, Gupta KC. Novel polyethylenimine-derived nanoparticles for in vivo gene delivery. Expert Opin. Drug Deliv. 2013;10:215-228.
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300.
Jiang C, et al. Recent advances in the development of polyethylenimine-based gene vectors for safe and efficient gene delivery. Expert Opin. Drug Deliv. 2019;16:363-376.
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301.
Wang X, Niu D, Hu C, Li P. Polyethyleneimine-based nanocarriers for gene delivery. Curr. Pharm. Des. 2015;21:6140-6156.
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302.
Zhang YH, et al. Recycling gene carrier with high efficiency and low toxicity mediated by L-cystine-bridged bis(beta-cyclodextrin)s. Sci. Rep. 2014;4:7471.
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303.
Ke X, et al. Surface-functionalized PEGylated nanoparticles deliver messenger rna to pulmonary immune cells. ACS Appl. Mater. Interfaces. 2020;12:35835-35844.
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304.
Chen J, et al. Peptide-based and polypeptide-based gene delivery systems. Top. Curr. Chem. 2017;375:32.
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305.
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306.
Djafari J, et al. Study and preparation of multifunctional poly(L-Lysine)@hyaluronic acid nanopolyplexes for the effective delivery of tumor suppressive mir-34a into triple-negative breast cancer cells. Mater. (Basel). 2020;13:5309.
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307.
Li J, et al. Copolymer of poly(ethylene glycol) and poly(L-lysine) grafting polyethylenimine through a reducible disulfide linkage for siRNA delivery. Nanoscale. 2014;6:1732-1740.
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308.
Yang W, et al. Polymeric Micelles with pH-responsive cross-linked core enhance in vivo mrna delivery. Pharmaceutics. 2022;14:1205.
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309.
Cell-penetrating peptides and their analogues as novel nanocarriers for drug delivery · 2015
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310.
Debacker AJ, et al. Delivery of oligonucleotides to the liver with GalNAc: from research to registered therapeutic drug. Mol. Ther. 2020;28:1759-1771.
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311.
Nair JK, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 2014;136:16958-16961.
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Cui H, et al. Liver-targeted delivery of oligonucleotides with N-acetylgalactosamine conjugation. ACS Omega. 2021;6:16259-16265.
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313.
Investigating the pharmacodynamic durability of GalNAc–siRNA conjugates · 2020
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314.
Abdelaal AM, Kasinski AL. Ligand-mediated delivery of RNAi-based therapeutics for the treatment of oncological diseases. NAR Cancer. 2021;3:zcab030.
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315.
Huang X, Leroux JC, Castagner B. Well-defined multivalent ligands for hepatocytes targeting via asialoglycoprotein receptor. Bioconjugate Chem. 2017;28:283-295.
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316.
Delivery of GalNAc-Conjugated Splice-Switching ASOs to Non-hepatic Cells through Ectopic Expression of Asialoglycoprotein Receptor · 2019
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317.
Thangamani L, et al. GalNAc-siRNA conjugates: prospective tools on the frontier of anti-viral therapeutics. Pharmacol. Res. 2021;173:105864.
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318.
Nair JK, et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res. 2017;45:10969-10977.
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319.
Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates · 2018
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320.
Hassler MR, et al. Comparison of partially and fully chemically-modified siRNA in conjugate-mediated delivery in vivo. Nucleic Acids Res. 2018;46:2185-2196.
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321.
Parmar RG, et al. Facile synthesis, geometry, and 2’-substituent-dependent in vivo activity of 5’-(E)- and 5’-(Z)-vinylphosphonate-modified siRNA conjugates. J. Med. Chem. 2018;61:734-744.
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322.
Janas MM, et al. Safety evaluation of 2’-deoxy-2’-fluoro nucleotides in GalNAc-siRNA conjugates. Nucleic Acids Res. 2019;47:3306-3320.
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323.
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Not in our library10.1023/b:glyc.0000045095.86867.c0
324.
Rensen PC, et al. Determination of the upper size limit for uptake and processing of ligands by the asialoglycoprotein receptor on hepatocytes in vitro and in vivo. J. Biol. Chem. 2001;276:37577-37584.
Not in our library10.1074/jbc.m101786200
325.
Schmidt K, et al. Characterizing the effect of GalNAc and phosphorothioate backbone on binding of antisense oligonucleotides to the asialoglycoprotein receptor. Nucleic Acids Res. 2017;45:2294-2306.
Not in our library10.1093/nar/gkx060
326.
Lee YC, et al. Binding of synthetic oligosaccharides to the hepatic Gal/GalNAc lectin. dependence on fine structural features. J. Biol. Chem. 1983;258:199-202.
Not in our library10.1016/s0021-9258(18)33240-x
327.
Biessen EA, et al. Synthesis of cluster galactosides with high affinity for the hepatic asialoglycoprotein receptor. J. Med. Chem. 1995;38:1538-1546.
Not in our library10.1021/jm00009a014
328.
Kichler A, Schuber F. Versatile synthesis of bi- and tri-antennary galactose ligands: interaction with the Gal/GalNAc receptor of human hepatoma cells. Glycoconj. J. 1995;12:275-281.
Not in our library10.1007/bf00731330
329.
Huang Y. Preclinical and clinical advances of GalNAc-decorated nucleic acid therapeutics. Mol. Ther. Nucl. Acids. 2017;6:116-132.
Not in our library10.1016/j.omtn.2016.12.003
330.
Syed YY. Nedosiran: first approval. Drugs. 2023;83:1729-1733.
Not in our library10.1007/s40265-023-01976-4
331.
Xu H, Liao C, Liang S, Ye BC. A novel peptide-equipped exosomes platform for delivery of antisense oligonucleotides. ACS Appl. Mater. Interfaces. 2021;13:10760-10767.
Not in our library10.1021/acsami.1c00016
332.
Crescitelli R, Lasser C, Lotvall J. Isolation and characterization of extracellular vesicle subpopulations from tissues. Nat. Protoc. 2021;16:1548-1580.
Not in our library10.1038/s41596-020-00466-1
333.
Delorme-Axford E, et al. Human placental trophoblasts confer viral resistance to recipient cells. Proc. Natl Acad. Sci. USA. 2013;110:12048-12053.
Not in our library10.1073/pnas.1304718110
334.
Yang T, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in danio rerio. Pharm. Res. 2015;32:2003-2114.
Not in our library10.1007/s11095-014-1593-y
335.
Su SA, et al. Emerging role of exosome-mediated intercellular communication in vascular remodeling. Oncotarget. 2017;8:25700-25712.
Not in our library10.18632/oncotarget.14878
336.
Pegtel DM, Gould SJ. Exosomes. Annu. Rev. Biochem. 2019;88:487-514.
Not in our library10.1146/annurev-biochem-013118-111902
337.
Wang JJ, et al. Macrophage-secreted exosomes delivering miRNA-21 inhibitor can regulate BGC-823 cell proliferation. Asian Pac. J. Cancer Prev. 2015;16:4203-4209.
Not in our library10.7314/apjcp.2015.16.10.4203
338.
Zheng H, et al. Exosome‑encapsulated miR‑26a attenuates aldosterone‑induced tubulointerstitial fibrosis by inhibiting the CTGF/SMAD3 signaling pathway. Int. J. Mol. Med. 2023;51:11.
Not in our library10.3892/ijmm.2022.5214
339.
Hashemi ZS, et al. Novel delivery of sorafenib by natural killer cell-derived exosomes-enhanced apoptosis in triple-negative breast cancer. Nanomed. (Lond.). 2023;18:437-453.
Not in our library10.2217/nnm-2022-0237
340.
Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity · 2022
No notice
341.
Kaban K, et al. Therapeutic silencing of BCL-2 using NK cell-derived exosomes as a novel therapeutic approach in breast cancer. Cancers (Basel). 2021;13:2397.
Not in our library10.3390/cancers13102397
342.
Wahlgren J, et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 2012;40:e130.
Not in our library10.1093/nar/gks463
343.
Alvarez-Erviti L, et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011;29:341-345.
Not in our library10.1038/nbt.1807
344.
Yuan D, et al. Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain. Biomaterials. 2017;142:1-12.
Not in our library10.1016/j.biomaterials.2017.07.011
345.
Zheng M, et al. Harnessing exosomes for the development of brain drug delivery systems. Bioconjugate Chem. 2019;30:994-1005.
Not in our library10.1021/acs.bioconjchem.9b00085
346.
Recent advancements in the use of exosomes as drug delivery systems · 2018
No notice
347.
Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives · 2022
No notice
348.
Asadirad A, et al. Dendritic cell immunotherapy with miR-155 enriched tumor-derived exosome suppressed cancer growth and induced antitumor immune responses in murine model of colorectal cancer induced by CT26 cell line. Int. Immunopharmacol. 2022;104:108493.
Not in our library10.1016/j.intimp.2021.108493
349.
Xi XM, Xia SJ, Lu R. Drug loading techniques for exosome-based drug delivery systems. Pharmazie. 2021;76:61-67.
Not in our library10.1691/ph.2021.0128
350.
Kim MS, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12:655-664.
Not in our library10.1016/j.nano.2015.10.012
351.
Delivery of Anti-miRNA-221 for Colorectal Carcinoma Therapy Using Modified Cord Blood Mesenchymal Stem Cells-Derived Exosomes · 2021
Not checked
352.
Luan X, et al. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacol. Sin. 2017;38:754-763.
Not in our library10.1038/aps.2017.12
353.
Rehman FU, Liu Y, Zheng M, Shi B. Exosomes based strategies for brain drug delivery. Biomaterials. 2023;293:121949.
Not in our library10.1016/j.biomaterials.2022.121949
354.
Johnsen KB, et al. Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes. Cytotechnology. 2016;68:2125-2138.
Not in our library10.1007/s10616-016-9952-7
355.
Engineering exosomes for targeted drug delivery · 2021
No notice
356.
Exosome-mediated targeted delivery of miR-210 for angiogenic therapy after cerebral ischemia in mice · 2019
No notice
357.
Kim G, et al. Systemic delivery of microRNA-21 antisense oligonucleotides to the brain using T7-peptide decorated exosomes. J. Control. Release. 2020;317:273-281.
Not in our library10.1016/j.jconrel.2019.11.009
358.
Mahati S, et al. Delivery of miR-26a using an exosomes-based nanosystem inhibited proliferation of hepatocellular carcinoma. Front. Mol. Biosci. 2021;8:738219.
Not in our library10.3389/fmolb.2021.738219
359.
Xu X, et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. Biomaterials. 2021;269:120539.
Not in our library10.1016/j.biomaterials.2020.120539
360.
Systemic exosomal siRNA delivery reduced alpha‐synuclein aggregates in brains of transgenic mice · 2014
No notice
361.
Ren X, et al. Exosomal DNA aptamer targeting alpha-synuclein aggregates reduced neuropathological deficits in a mouse parkinson’s disease model. Mol. Ther. Nucl. Acids. 2019;17:726-740.
Not in our library10.1016/j.omtn.2019.07.008
362.
Fu Z, et al. In vivo self-assembled small RNAs as a new generation of RNAi therapeutics. Cell Res. 2021;31:631-648.
Not in our library10.1038/s41422-021-00491-z
363.
A brief history of nearly EV‐erything – The rise and rise of extracellular vesicles · 2021
No notice
364.
Erathodiyil N, Ying JY. Functionalization of inorganic nanoparticles for bioimaging applications. Acc. Chem. Res. 2011;44:925-935.
Not in our library10.1021/ar2000327
365.
Meena J, et al. Inorganic nanoparticles for natural product delivery: a review. Environ. Chem. Lett. 2020;18:2107-2118.
Not in our library10.1007/s10311-020-01061-2
366.
Luther DC, et al. Delivery of drugs, proteins, and nucleic acids using inorganic nanoparticles. Adv. Drug Deliv. Rev. 2020;156:188-213.
Not in our library10.1016/j.addr.2020.06.020
367.
Wang Z, et al. Gold nanoparticle‑mediated delivery of paclitaxel and nucleic acids for cancer therapy (Review). Mol. Med. Rep. 2020;22:4475-4484.
Not in our library10.3892/mmr.2020.11580
368.
Graczyk A, Pawlowska R, Jedrzejczyk D, Chworos A. Gold nanoparticles in conjunction with nucleic acids as a modern molecular system for cellular delivery. Molecules. 2020;25:204.
Not in our library10.3390/molecules25010204
369.
Shrestha B, et al. Gold nanoparticles mediated drug-gene combinational therapy for breast cancer treatment. Int. J. Nanomed. 2020;15:8109-8119.
Not in our library10.2147/ijn.s258625
370.
Jensen SA, et al. Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci. Transl. Med. 2013;5:209ra152.
Not in our library10.1126/scitranslmed.3006839
371.
Kumthekar P, et al. A first-in-human phase 0 clinical study of RNA interference-based spherical nucleic acids in patients with recurrent glioblastoma. Sci. Transl. Med. 2021;13:eabb3945.
Not in our library10.1126/scitranslmed.abb3945
372.
Wu K, et al. Magnetic nanoparticles in nanomedicine: a review of recent advances. Nanotechnology. 2019;30:502003.
Not in our library10.1088/1361-6528/ab4241
373.
Dash S, et al. Emerging trends in the nanomedicine applications of functionalized magnetic nanoparticles as novel therapies for acute and chronic diseases. J. Nanobiotechnol. 2022;20:393.
Not in our library10.1186/s12951-022-01595-3
374.
Chavan N, Dharmaraj D, Sarap S, Surve C. Magnetic nanoparticles–new era in nanotechnology. J. Drug Deliv. Sci. Technol. 2022;77:103899.
Not in our library10.1016/j.jddst.2022.103899
375.
Luo M, et al. Delivering the promise of gene therapy with nanomedicines in treating central nervous system diseases. Adv. Sci. 2022;9:e2201740.
Not in our library10.1002/advs.202201740
376.
Rahamathulla M, et al. Carbon nanotubes: current perspectives on diverse applications in targeted drug delivery and therapies. Mater. (Basel). 2021;14:6707.
Not in our library10.3390/ma14216707
377.
Ren X, et al. Photoactivatable RNAi for cancer gene therapy triggered by near-infrared-irradiated single-walled carbon nanotubes. Int. J. Nanomed. 2017;12:7885-7896.
Not in our library10.2147/ijn.s141882
378.
Levina AS, Repkova MN, Ismagilov ZR, Zarytova VF. Methods of the synthesis of silicon-containing nanoparticles intended for nucleic acid delivery. Eurasia. Chem.-Techno. 2018;20:177-194.
Not in our library10.18321/ectj720
379.
Stead SO, et al. siRNA gene knockdown with functionalised porous silicon nanoparticles. Transplantation. 2020;104:s158.
Not in our library10.1097/01.tp.0000699128.55216.db
380.
Luo M, et al. A multifunctional porous silicon nanocarrier for glioblastoma treatment. Mol. Pharmaceutics. 2023;20:545-560.
Not in our library10.1021/acs.molpharmaceut.2c00763
381.
Goyal R, et al. Peptide-based delivery vectors with pre-defined geometrical locks. RSC Med. Chem. 2020;11:1303-1313.
Not in our library10.1039/d0md00229a
382.
Lian Z, Ji T. Functional peptide-based drug delivery systems. J. Mater. Chem. B. 2020;8:6517-6529.
Not in our library10.1039/d0tb00713g
383.
Jeon BW, et al. Recent advances in peptide signaling during arabidopsis root development. J. Exp. Bot. 2021;72:2889-2902.
Not in our library10.1093/jxb/erab050
384.
Kim J, et al. Oral supplementation of low-molecular-weight collagen peptides reduces skin wrinkles and improves biophysical properties of skin: a randomized, double-blinded, placebo-controlled study. J. Med. Food. 2022;25:1146-1154.
Not in our library10.1089/jmf.2022.k.0097
385.
Lindberg J, Nilvebrant J, Nygren, P A, Lehmann F. Progress and future directions with peptide-drug conjugates for targeted cancer therapy. Molecules. 2021;26:6042.
Not in our library10.3390/molecules26196042
386.
Hao C, et al. Renovation of old drugs’ – can peptide drug conjugates lead the post-ADC era? Aust. J. Chem. 2023;76:318-336.
Not in our library10.1071/ch22252
387.
Wang J, Tripathy N, Chung EJ. Targeting and therapeutic peptide-based strategies for polycystic kidney disease. Adv. Drug Deliv. Rev. 2020;161-162:176-189.
Not in our library10.1016/j.addr.2020.08.011
388.
Feldman KS, Pavlou MP, Zahid M. Cardiac targeting peptide: from identification to validation to mechanism of transduction. Methods Mol. Biol. 2021;2211:97-112.
Not in our library10.1007/978-1-0716-0943-9_8
389.
Lu L, et al. A novel blood-brain barrier-penetrating and vascular-targeting chimeric peptide inhibits glioma angiogenesis. Int. J. Mol. Sci. 2023;24:8753.
Not in our library10.3390/ijms24108753
390.
Suzuki M, et al. Characterization of the membrane penetration-enhancing peptide S19 derived from human syncytin-1 for the intracellular delivery of TAT-fused proteins. Biochem. Biophys. Res. Commun. 2022;586:63-67.
Not in our library10.1016/j.bbrc.2021.11.065
391.
Vijakumaran U, et al. Development of cell penetrating peptides for effective delivery of recombinant factors into target cells. Protein Pept. Lett. 2020;27:1092-1101.
Not in our library10.2174/0929866527666200525164135
392.
Maraming P, et al. The cationic cell-penetrating KT2 peptide promotes cell membrane defects and apoptosis with autophagy inhibition in human HCT 116 colon cancer cells. J. Cell. Physiol. 2019;234:22116-22129.
Not in our library10.1002/jcp.28774
393.
Klipp A, Burger M, Leroux JC. Get out or die trying: peptide- and protein-based endosomal escape of RNA therapeutics. Adv. Drug Deliv. Rev. 2023;200:115047.
Not in our library10.1016/j.addr.2023.115047
394.
Guo Y, et al. Self-assembled peptide nanoparticles with endosome escaping permits for co-drug delivery. Talanta. 2021;221:121572.
Not in our library10.1016/j.talanta.2020.121572
395.
Zhao, Y. et al. Engineered histidine-rich peptides enhance endosomal escape for antibody-targeted intracellular delivery of functional proteins. Angew. Chem. Int. Ed. e202304692 (2023).
Not in our library10.1002/anie.202304692
396.
Types of nuclear localization signals and mechanisms of protein import into the nucleus · 2021
No notice
397.
Huang S, et al. Design of acid-activated cell-penetrating peptides with nuclear localization capacity for anticancer drug delivery. J. Pept. Sci. 2021;27:e3354.
Not in our library10.1002/psc.3354
398.
Kanazawa T, et al. Electroporation-based ex vivo gene delivery into dendritic cells by anionic polymer-coated versatile nuclear localization signal/pDNA complex. Biol. Pharm. Bull. 2021;44:1866-1871.
Not in our library10.1248/bpb.b21-00559
399.
Urandur S, Sullivan MO. Peptide-based vectors: a biomolecular engineering strategy for gene delivery. Annu. Rev. Chem. Biomol. Eng. 2023;14:243-264.
Not in our library10.1146/annurev-chembioeng-101121-070232
400.
Varanko A, Saha S, Chilkoti A. Recent trends in protein and peptide-based biomaterials for advanced drug delivery. Adv. Drug Deliv. Rev. 2020;156:133-187.
Not in our library10.1016/j.addr.2020.08.008
401.
Falato L, Gestin M, Langel U. Cell-penetrating peptides delivering siRNAs: an overview. Methods Mol. Biol. 2021;2282:329-352.
Not in our library10.1007/978-1-0716-1298-9_18
402.
Kim EH, et al. PDL1-binding peptide/anti-miRNA21 conjugate as a therapeutic modality for PD-L1(high) tumors and TAMs. J. Control. Release. 2022;345:62-74.
Not in our library10.1016/j.jconrel.2022.02.031
403.
Yang G, et al. Improved cellular delivery of antisense oligonucleotide for miRNA-21 imaging in vivo using cell-penetrating peptide-based nanoprobes. Mol. Pharmaceutics. 2021;18:787-795.
Not in our library10.1021/acs.molpharmaceut.0c00160
404.
Liu Q, et al. iRGD-modified exosomes-delivered BCL6 siRNA inhibit the progression of diffuse large B-cell lymphoma. Front. Oncol. 2022;12:822805.
Not in our library10.3389/fonc.2022.822805
405.
Khabazian E, et al. Cationic liposome decorated with cyclic RGD peptide for targeted delivery of anti-STAT3 siRNA to melanoma cancer cells. J. Drug Target. 2022;30:522-533.
Not in our library10.1080/1061186x.2021.1973481
406.
A bivalent cyclic RGD–siRNA conjugate enhances the antitumor effect of apatinib via co-inhibiting VEGFR2 in non-small cell lung cancer xenografts · 2021
Not checked
407.
Liu X, et al. Tumor-targeted in vivo gene silencing via systemic delivery of cRGD-conjugated siRNA. Nucleic Acids Res. 2014;42:11805-11817.
Not in our library10.1093/nar/gku831
408.
Wang Y, et al. Tumor-targeted anti-VEGF RNAi capable of sequentially responding to intracellular microenvironments for potent systemic tumor suppression. ACS Appl. Bio Mater. 2020;3:9145-9155.
Not in our library10.1021/acsabm.0c01427
409.
Moshnikova A, et al. Targeting bladder urothelial carcinoma with pHLIP-ICG and inhibition of urothelial cancer cell proliferation by pHLIP-amanitin. Front Urol. 2022;2:868919.
Not in our library10.3389/fruro.2022.868919
410.
Zhang M, et al. In vivo distribution and therapeutic efficacy of radioiodine-labeled pH-low insertion peptide variant 3 in a mouse model of breast cancer. Mol. Imaging. 2022;2022:7456365.
Not in our library10.1155/2022/7456365
411.
Wyatt LC, et al. Applications of pHLIP technology for cancer imaging and therapy. Trends Biotechnol. 2017;35:653-664.
Not in our library10.1016/j.tibtech.2017.03.014
412.
Dupont M, et al. Tumor treatment by pHLIP-targeted antigen delivery. Front. Bioeng. Biotech. 2022;10:1082290.
Not in our library10.3389/fbioe.2022.1082290
413.
Visca H, et al. pHLIP peptides target acidity in activated macrophages. Mol. Imaging Biol. 2022;24:874-885.
Not in our library10.1007/s11307-022-01737-x
414.
Son SM, et al. Therapeutic effect of pHLIP-mediated CEACAM6 gene silencing in lung adenocarcinoma. Sci. Rep. 2019;9:11607.
Not in our library10.1038/s41598-019-48104-5
415.
Luna Velez MV, et al. Delivery of antisense oligonucleotides for splice-correction of androgen receptor pre-mRNA in castration-resistant prostate cancer models using cell-penetrating peptides. Prostate. 2022;82:657-665.
Not in our library10.1002/pros.24309
416.
Ervin EH, et al. Targeted gene silencing in human embryonic stem cells using cell-penetrating peptide PepFect 14. Stem Cell Res. Ther. 2019;10:43.
Not in our library10.1186/s13287-019-1144-x
417.
Kurrikoff K, Vunk B, Langel U. Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics. Expert Opin. Biol. Ther. 2021;21:361-370.
Not in our library10.1080/14712598.2021.1823368
418.
Taniguchi K, et al. Alpha-aminoisobutyric acid-containing amphipathic helical peptide-cyclic RGD conjugation as a potential drug delivery system for microRNA replacement therapy in vitro. Mol. Pharmaceutics. 2019;16:4542-4550.
Not in our library10.1021/acs.molpharmaceut.9b00680
419.
Tarvirdipour S, et al. A self-assembling peptidic platform to boost the cellular uptake and nuclear delivery of oligonucleotides. Biomater. Sci. 2022;10:4309-4323.
Not in our library10.1039/d2bm00826b
420.
Ji K, Xiao Y, Zhang W. Acid-activated nonviral peptide vector for gene delivery. J. Pept. Sci. 2020;26:e3230.
Not in our library10.1002/psc.3230
421.
Kwon EJ, Ko H, Bhatia SN. Peptide spiders: peptide-polymer conjugates to traffic nucleic acids. Mol. Pharmaceutics. 2020;17:3633-3642.
Not in our library10.1021/acs.molpharmaceut.0c00714
422.
Kim GC, Cheon DH, Lee Y. Challenge to overcome current limitations of cell-penetrating peptides. BBA Proteins Proteom. 2021;1869:140604.
Not in our library10.1016/j.bbapap.2021.140604
423.
Hadianamrei R, Zhao X. Current state of the art in peptide-based gene delivery. J. Control. Release. 2022;343:600-619.
Not in our library10.1016/j.jconrel.2022.02.010
424.
Buyanova M, et al. Discovery of a cyclic cell-penetrating peptide with improved endosomal escape and cytosolic delivery efficiency. Mol. Pharmaceutics. 2022;19:1378-1388.
Not in our library10.1021/acs.molpharmaceut.1c00924
425.
Molle LM, Smyth CH, Yuen D, Johnston APR. Nanoparticles for vaccine and gene therapy: overcoming the barriers to nucleic acid delivery. WIREs Nanomed. Nanobiotechnol. 2022;14:e1809.
Not in our library10.1002/wnan.1809
426.
Alhakamy NA, Nigatu AS, Berkland CJ, Ramsey JD. Noncovalently associated cell-penetrating peptides for gene delivery applications. Ther. Deliv. 2013;4:741-757.
Not in our library10.4155/tde.13.44
427.
Peptide-based delivery of therapeutics in cancer treatment · 2022
Not checked
428.
Burks SR, et al. Co-encapsulating the fusogenic peptide INF7 and molecular imaging probes in liposomes increases intracellular signal and probe retention. PLoS One. 2015;10:e0120982.
Not in our library10.1371/journal.pone.0120982
429.
Feng R, Ni R, Chau Y. Fusogenic peptide modification to enhance gene delivery by peptide-DNA nano-coassemblies. Biomater. Sci. 2022;10:5116-5120.
Not in our library10.1039/d2bm00705c
430.
Hagino Y, et al. GALA-modified lipid nanoparticles for the targeted delivery of plasmid dna to the lungs. Mol. Pharmaceutics. 2021;18:878-888.
Not in our library10.1021/acs.molpharmaceut.0c00854
431.
Li C, Cao XW, Zhao J, Wang FJ. Effective therapeutic drug delivery by GALA3, an endosomal escape peptide with reduced hydrophobicity. J. Membr. Biol. 2020;253:139-152.
Not in our library10.1007/s00232-020-00109-2
432.
Miura N, et al. A KALA-modified lipid nanoparticle containing CpG-free plasmid DNA as a potential DNA vaccine carrier for antigen presentation and as an immune-stimulative adjuvant. Nucleic Acids Res. 2015;43:1317-1331.
Not in our library10.1093/nar/gkv008
433.
Dastpeyman M, et al. Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides. Int. J. Pharm. 2021;599:120398.
Not in our library10.1016/j.ijpharm.2021.120398
434.
Alipour M, Hosseinkhani S, Sheikhnejad R, Cheraghi R. Nano-biomimetic carriers are implicated in mechanistic evaluation of intracellular gene delivery. Sci. Rep. 2017;7:41507.
Not in our library10.1038/srep41507
435.
Samec T, et al. Fusogenic peptide delivery of bioactive siRNAs targeting CSNK2A1 for treatment of ovarian cancer. Mol. Ther. Nucl. Acids. 2022;30:95-111.
Not in our library10.1016/j.omtn.2022.09.012
436.
Lu S, et al. Multi-functional self-assembled nanoparticles for pVEGF-shRNA loading and anti-tumor targeted therapy. Int. J. Pharm. 2020;575:118898.
Not in our library10.1016/j.ijpharm.2019.118898
437.
The Significance of Mitochondrial Dysfunction in Cancer · 2020
No notice
438.
Yao RQ, Ren C, Xia ZF, Yao YM. Organelle-specific autophagy in inflammatory diseases: a potential therapeutic target underlying the quality control of multiple organelles. Autophagy. 2021;17:385-401.
Not in our library10.1080/15548627.2020.1725377
439.
Machado-Oliveira G, Ramos C, Marques ARA, Vieira OV. Cell senescence, multiple organelle dysfunction and atherosclerosis. Cells. 2020;9:2146.
Not in our library10.3390/cells9102146
440.
Hu C, Huang Y, Chen Y. Targeted modification of the cationic anticancer peptide HPRP-A1 with iRGD to improve specificity, penetration, and tumor-tissue accumulation. Mol. Pharmaceutics. 2019;16:561-572.
Not in our library10.1021/acs.molpharmaceut.8b00854
441.
Nakamura M, Fujiwara K, Doi N. Cytoplasmic delivery of siRNA using human-derived membrane penetration-enhancing peptide. J. Nanobiotechnol. 2022;20:458.
Not in our library10.1186/s12951-022-01667-4
442.
Bjorge JD, Pang A, Fujita DJ. Delivery of gene targeting siRNAs to breast cancer cells using a multifunctional peptide complex that promotes both targeted delivery and endosomal release. PLoS One. 2017;12:e0180578.
Not in our library10.1371/journal.pone.0180578
443.
Ruan R, et al. Topical and targeted delivery of sirnas to melanoma cells using a fusion peptide carrier. Sci. Rep. 2016;6:29159.
Not in our library10.1038/srep29159
444.
Cerrato CP, et al. Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides. J. Mater. Chem. B. 2020;8:10825-10836.
Not in our library10.1039/d0tb01106a
445.
Kuang Y, et al. Dual functional peptide-driven nanoparticles for highly efficient glioma-targeting and drug codelivery. Mol. Pharmaceutics. 2016;13:1599-1607.
Not in our library10.1021/acs.molpharmaceut.6b00051
446.
Bulut S, et al. Slow release and delivery of antisense oligonucleotide drug by self-assembled peptide amphiphile nanofibers. Biomacromolecules. 2011;12:3007-3014.
Not in our library10.1021/bm200641e
447.
Nirasawa K, et al. Development of A2G80 peptide-gene complex for targeted delivery to muscle cells. J. Control. Release. 2021;329:988-996.
Not in our library10.1016/j.jconrel.2020.10.029
448.
Jafari M, Chen P. Peptide mediated siRNA delivery. Curr. Top. Med. Chem. 2009;9:1088-1097.
Not in our library10.2174/156802609789630839
449.
Yan Y. Q. et al. Localized instillation enables in vivo screening of targeting peptides using one-bead one-compound technology. ACS Nano. 10.1021/acsnano.2c09894 (2023).
Not in our library10.1021/acsnano.2c09894
450.
Paray BA, et al. The role of the multifunctional antimicrobial peptide melittin in gene delivery. Drug. Discov. Today. 2021;26:1053-1059.
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451.
Govindarajan S, et al. Targeting human epidermal growth factor receptor 2 by a cell-penetrating peptide-affibody bioconjugate. Biomaterials. 2012;33:2570-2582.
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452.
Li Q, et al. Multifunctional peptide-conjugated nanocarriers for pulp regeneration in a full-length human tooth root. Acta Biomater. 2021;127:252-265.
Not in our library10.1016/j.actbio.2021.03.059
453.
Wan Y, Moyle PM, Christie MP, Toth I. Nanosized, peptide-based multicomponent DNA delivery systems: optimization of endosome escape activity. Nanomed. (Lond.). 2016;11:907-919.
Not in our library10.2217/nnm.16.27
454.
Rohira H, Arora A, Kaur P, Chugh A. Peptide cargo administration: current state and applications. Appl. Microbiol. Biotechnol. 2023;107:3153-3181.
Not in our library10.1007/s00253-023-12512-5
455.
Liu Y, et al. Development and characterization of high efficacy cell-penetrating peptide via modulation of the histidine and arginine ratio for gene therapy. Mater. (Basel). 2021;14:4674.
Not in our library10.3390/ma14164674
456.
Tsvetkov VB, et al. Anticoagulant oligonucleotide-peptide conjugates: identification of thrombin aptamer conjugates with improved characteristics. Int. J. Mol. Sci. 2022;23:3820.
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457.
Kaplan AR, et al. Ku80-targeted pH-sensitive peptide-PNA conjugates are tumor selective and sensitize cancer cells to ionizing radiation. Mol. Cancer Res. 2020;18:873-882.
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458.
Dutta K, Das R, Medeiros J, Thayumanavan S. Disulfide bridging strategies in viral and nonviral platforms for nucleic acid delivery. Biochemistry. 2021;60:966-990.
Not in our library10.1021/acs.biochem.0c00860
459.
Taskova M, Mantsiou A, Astakhova K. Synthetic nucleic acid analogues in gene therapy: an update for peptide-oligonucleotide conjugates. Chembiochem. 2017;18:1671-1682.
Not in our library10.1002/cbic.201700229
460.
Klabenkova K, Fokina A, Stetsenko D. Chemistry of peptide-oligonucleotide conjugates: a review. Molecules. 2021;26:5420.
Not in our library10.3390/molecules26175420
461.
Cerrato CP, Lehto T, Langel U. Peptide-based vectors: recent developments. Biomol. Concepts. 2014;5:479-488.
Not in our library10.1515/bmc-2014-0024
462.
Tomassi S, et al. Cationic nucleopeptides as novel non-covalent carriers for the delivery of peptide nucleic acid (PNA) and RNA oligomers. Bioorg. Med. Chem. 2018;26:2539-2550.
Not in our library10.1016/j.bmc.2018.04.017
463.
Hansen AM, Shaikh AY, Franzyk H. Facile preparation of pna-peptide conjugates with a polar maleimide-thioether linkage. Methods Mol. Biol. 2020;2105:97-118.
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464.
Schissel CK, et al. Cell-penetrating d-peptides retain antisense morpholino oligomer delivery activity. ACS Bio Med Chem. Au. 2022;2:150-160.
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465.
Hakata Y, et al. Intracellular delivery of a peptide nucleic acid-based hybrid of an autophagy inducing peptide with a cell-penetrating peptide. Org. Biomol. Chem. 2020;18:1978-1986.
Not in our library10.1039/c9ob02559f
466.
Linden G, et al. Efficient antisense inhibition reveals microRNA-155 to restrain a late-myeloid inflammatory programme in primary human phagocytes. RNA Biol. 2021;18:604-618.
Not in our library10.1080/15476286.2021.1885209
467.
Barkowsky G, et al. Antimicrobial activity of peptide-coupled antisense peptide nucleic acids in streptococcus pneumoniae. Microbiol Spectr. 2022;10:e0049722.
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468.
Soudah T, Mogilevsky M, Karni R, Yavin E. CLIP6-PNA-peptide conjugates: non-endosomal delivery of splice switching oligonucleotides. Bioconjugate Chem. 2017;28:3036-3042.
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469.
Sheng L, et al. Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model. Nucleic Acids Res. 2020;48:2853-2865.
Not in our library10.1093/nar/gkaa126
470.
Gushchina LV, et al. Systemic PPMO-mediated dystrophin expression in the Dup2 mouse model of duchenne muscular dystrophy. Mol. Ther. Nucl. Acids. 2022;30:479-492.
Not in our library10.1016/j.omtn.2022.10.025
471.
Aslesh T, et al. DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration. JCI Insight. 2023;8:e160516.
Not in our library10.1172/jci.insight.160516
472.
Gait MJ, et al. Cell-penetrating peptide conjugates of steric blocking oligonucleotides as therapeutics for neuromuscular diseases from a historical perspective to current prospects of treatment. Nucleic Acid Ther. 2019;29:1-12.
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473.
Hammond SM, et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc. Natl Acad. Sci. USA. 2016;113:10962-10967.
Not in our library10.1073/pnas.1605731113
474.
Blain AM, et al. Peptide-conjugated phosphodiamidate oligomer-mediated exon skipping has benefits for cardiac function in mdx and cmah-/-mdx mouse models of duchenne muscular dystrophy. PLoS One. 2018;13:e0198897.
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475.
Klein AF, et al. Peptide-conjugated oligonucleotides evoke long-lasting myotonic dystrophy correction in patient-derived cells and mice. J. Clin. Investig. 2019;129:4739-4744.
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476.
Chioccioli M, et al. A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis. EBioMedicine. 2022;85:104304.
Not in our library10.1016/j.ebiom.2022.104304
477.
Jana A, Narula P, Chugh A, Kulshreshtha R. Efficient delivery of anti-miR-210 using Tachyplesin, a cell penetrating peptide, for glioblastoma treatment. Int. J. Pharm. 2019;572:118789.
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478.
Schachner-Nedherer AL, et al. Biological activity of miRNA-27a using peptide-based drug delivery systems. Int. J. Nanomed. 2019;14:7795-7808.
Not in our library10.2147/ijn.s208446
479.
Xu W, et al. The mirrored cationic peptide as miRNA vehicle for efficient lung cancer therapy. MedComm. 2023;4:e273.
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480.
Wang J, et al. Strategies for improving the safety and RNAi efficacy of noncovalent peptide/siRNA nanocomplexes. Adv. Colloid Interface Sci. 2022;302:102638.
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481.
Ryu YC, Lee YE, Hwang BH. Efficient and safe small RNA delivery to macrophage using peptide-based nanocomplex. Biotechnol. Bioeng. 2022;119:482-492.
Not in our library10.1002/bit.27988
482.
Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment · 2022
No notice
483.
Wu LP, et al. Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide. Nat. Commun. 2019;10:4635.
Not in our library10.1038/s41467-019-12554-2
484.
Yan H, et al. Peptide-siRNA nanoparticles targeting NF-kappaB p50 mitigate experimental abdominal aortic aneurysm progression and rupture. Biomater. Adv. 2022;139:213009.
Not in our library10.1016/j.bioadv.2022.213009
485.
Yan H, et al. Induction of WNT16 via peptide-mRNA nanoparticle-based delivery maintains cartilage homeostasis. Pharmaceutics. 2020;12:73.
Not in our library10.3390/pharmaceutics12010073
486.
Jin Y, et al. Histone demethylase JMJD3 downregulation protects against aberrant force-induced osteoarthritis through epigenetic control of NR4A1. Int. J. Oral. Sci. 2022;14:34.
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487.
Zhou HF, et al. Peptide-siRNA nanocomplexes targeting NF-kappaB subunit p65 suppress nascent experimental arthritis. J. Clin. Investig. 2014;124:4363-4374.
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488.
Ceccanti M, Inghilleri M. RNA interference and neuromuscular diseases: a focus on hereditary transthyretin amyloidosis. Curr. Gene Ther. 2024;24:6-7.
Not in our library10.2174/1566523223666230913110011
489.
Adams D, Algalarrondo V, Echaniz-Laguna A. Hereditary transthyretin amyloidosis in the era of RNA interference, antisense oligonucleotide, and CRISPR-Cas9 treatments. Blood. 2023;142:1600-1612.
Not in our library10.1182/blood.2023019884
490.
Keam SJ. Inotersen: first global approval. Drugs. 2018;78:1371-1376.
Not in our library10.1007/s40265-018-0968-5
491.
Benson MD, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N. Engl. J. Med. 2018;379:22-31.
Not in our library10.1056/nejmoa1716793
492.
Coelho T, et al. Eplontersen for hereditary transthyretin amyloidosis with polyneuropathy. JAMA. 2023;330:1448-1458.
Not in our library10.1001/jama.2023.18688
493.
Keam SJ. Vutrisiran: first approval. Drugs. 2022;82:1419-1425.
Not in our library10.1007/s40265-022-01765-5
494.
Gillmore JD, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N. Engl. J. Med. 2021;385:493-502.
Not in our library10.1056/nejmoa2107454
495.
Happi Mbakam C, Tremblay JP. Gene therapy for duchenne muscular dystrophy: an update on the latest clinical developments. Expert Rev. Neurother. 2023;23:905-920.
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496.
Wagner KR, et al. Safety, tolerability, and pharmacokinetics of casimersen in patients with duchenne muscular dystrophy amenable to exon 45 skipping: a randomized, double-blind, placebo-controlled, dose-titration trial. Muscle Nerve. 2021;64:285-292.
Not in our library10.1002/mus.27347
497.
Syed YY. Eteplirsen: first global approval. Drugs. 2016;76:1699-1704.
Not in our library10.1007/s40265-016-0657-1
498.
Cirak S, et al. Exon skipping and dystrophin restoration in patients with duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study. Lancet. 2011;378:595-605.
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499.
Wilton-Clark H, Yokota T. Recent trends in antisense therapies for duchenne muscular dystrophy. Pharmaceutics. 2023;15:778.
Not in our library10.3390/pharmaceutics15030778
500.
Sheikh O, Yokota T. Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update. Arch. Toxicol. 2022;96:1-9.
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501.
Mellion M, et al. PGN-EDO51, an enhanced delivery oligonucleotide (EDO) for the treatment of duchenne muscular dystrophy (DMD): results of a phase 1 study in healthy volunteers (P3-8.004). Neurology. 2023;100:4396.
Not in our library10.1212/wnl.0000000000203955
502.
Van Daele SH, Masrori P, Van Damme P, Van Den Bosch L. The sense of antisense therapies in ALS. Trends Mol. Med. 2024;30:252-262.
Not in our library10.1016/j.molmed.2023.12.003
503.
Suzuki N, Nishiyama A, Warita H, Aoki M. Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy. J. Hum. Genet. 2023;68:131-152.
Not in our library10.1038/s10038-022-01055-8
504.
Fang T, et al. Gene therapy in amyotrophic lateral sclerosis. Cells. 2022;11:2066.
Not in our library10.3390/cells11132066
505.
Miller TM, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 2022;387:1099-1110.
Not in our library10.1056/nejmoa2204705
506.
Mccartan R, Khorkova O, Volmar CH, Wahlestedt C. Nucleic acid-based therapeutics for the treatment of central nervous system disorders. Front. Genet. 2023;14:1250276.
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507.
Nieto-Romero V, et al. Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts. iScience. 2024;27:109530.
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508.
Groothoff JW, et al. Clinical practice recommendations for primary hyperoxaluria: an expert consensus statement from ERKNet and OxalEurope. Nat. Rev. Nephrol. 2023;19:194-211.
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509.
Fargue S, Acquaviva Bourdain C. Primary hyperoxaluria type 1: pathophysiology and genetics. Clin. Kidney J. 2022;15:i4-i8.
Not in our library10.1093/ckj/sfab217
510.
Scott LJ, Keam SJ. Lumasiran: first approval. Drugs. 2021;81:277-282.
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511.
Lakhina Y, Boulis NM, Donsante A. Current and emerging targeted therapies for spinal muscular atrophy. Expert Rev. Neurother. 2023;23:1189-1199.
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512.
Ottesen EW, et al. Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic Acids Res. 2023;51:5948-5980.
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513.
Gowda VL, Fernandez-Garcia MA, Jungbluth H, Wraige E. New treatments in spinal muscular atrophy. Arch. Dis. Child. 2023;108:511-517.
Not in our library10.1136/archdischild-2021-323605
514.
Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment · 2023
No notice
515.
Singh NN, Howell MD, Androphy EJ, Singh RN. How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Ther. 2017;24:520-526.
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516.
De Vivo DC, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: interim efficacy and safety results from the phase 2 nurture study. Neuromuscul. Disord. 2019;29:842-856.
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517.
Montes J, et al. Nusinersen improves walking distance and reduces fatigue in later-onset spinal muscular atrophy. Muscle Nerve. 2019;60:409-414.
Not in our library10.1002/mus.26633
518.
Finkel RS, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: final report of a phase 2, open-label, multicentre, dose-escalation study. Lancet Child Adolesc. Health. 2021;5:491-500.
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519.
Neuzillet C, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol. Ther. 2015;147:22-31.
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520.
Andrews DW, et al. Phase Ib clinical trial of IGV-001 for patients with newly diagnosed glioblastoma. Clin. Cancer Res. 2021;27:1912-1922.
Not in our library10.1158/1078-0432.ccr-20-3805
521.
Lee IY, et al. Autologous cell immunotherapy (IGV-001) with IGF-1R antisense oligonucleotide in newly diagnosed glioblastoma patients. Future Oncol. 2024;20:579-591.
Not in our library10.2217/fon-2023-0702
522.
Weber JS, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet. 2024;403:632-644.
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523.
Yao R, Xie C, Xia X. Recent progress in mRNA cancer vaccines. Hum. Vaccines Immunother. 2024;20:2307187.
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524.
Nashine S. Potential therapeutic candidates for age-related macular degeneration (AMD). Cells. 2021;10:2483.
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525.
Nakamura Y. Multiple therapeutic applications of RBM-007, an anti-FGF2 aptamer. Cells. 2021;10:1617.
Not in our library10.3390/cells10071617
526.
Jimenez A, et al. SYL1801: preclinical efficacy and safety of a sirna-based eye drops treatment for age related macular degeneration. Investig. Ophthalmol. Vis. Sci. 2019;60:5389.
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527.
Jimenez AI, Ruz V, Vargas B, Bleau AM. Phase I of SYL1801, a new siRNA delivered in eye drops for age-related macular degeneration. Investig. Ophthalmol. Vis. Sci. 2022;63:337-F0168.
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528.
Moreno-Montanes J, Bleau AM, Jimenez AI. Tivanisiran, a novel siRNA for the treatment of dry eye disease. Expert Opin. Investig. Drugs. 2018;27:421-426.
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529.
Valdes-Arias D, et al. Recent United States developments in the pharmacological treatment of dry eye disease. Drugs. 2024;84:549-563.
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530.
Kuo YK, et al. Dry eye disease: a review of epidemiology in taiwan, and its clinical treatment and merits. J. Clin. Med. 2019;8:1227.
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531.
Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models · 2018
No notice
532.
Cideciyan AV, et al. Durable vision improvement after a single intravitreal treatment with antisense oligonucleotide in CEP290-LCA: replication in two eyes. Am. J. Ophthalmol. Case Rep. 2023;32:101873.
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533.
Dulla K, et al. Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Mol. Ther. 2021;29:2441-2455.
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534.
Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials · 2022
No notice
535.
Mhaimeed O, et al. The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: lower for longer is better. Am. J. Prev. Cardiol. 2024;18:100649.
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536.
Sawhney JP, et al. CSI clinical practice guidelines for dyslipidemia management: Executive summary. Indian Heart J. 2024;76:S6-S19.
Not in our library10.1016/j.ihj.2023.11.271
537.
Hummelgaard S, et al. Targeting PCSK9 to tackle cardiovascular disease. Pharmacol. Ther. 2023;249:108480.
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538.
Ferri N, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220:381-386.
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539.
Lamb YN. Inclisiran: first approval. Drugs. 2021;81:389-395.
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540.
Ray KK, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N. Engl. J. Med. 2020;382:1507-1519.
Not in our library10.1056/nejmoa1912387
541.
Ray KK, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur. Heart J. 2023;44:129-138.
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542.
Tsimikas S, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 2020;382:244-255.
Not in our library10.1056/nejmoa1905239
543.
Vinci P, et al. Lipoprotein(a) as a risk factor for cardiovascular diseases: pathophysiology and treatment perspectives. Int. J. Environ. Res. Public Health. 2023;20:6721.
Not in our library10.3390/ijerph20186721
544.
The relationship between lipoprotein(a) and risk of cardiovascular disease: a Mendelian randomization analysis · 2022
Not checked
545.
Malick WA, Goonewardena SN, Koenig W, Rosenson RS. Clinical trial design for lipoprotein(a)-lowering therapies: JACC focus seminar 2/3. J. Am. Coll. Cardiol. 2023;81:1633-1645.
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546.
Nissen SE, et al. Lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a): a randomized dose-ascending clinical trial. JAMA. 2023;330:2075-2083.
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547.
O’donoghue ML, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N. Engl. J. Med. 2022;387:1855-1864.
Not in our library10.1056/nejmoa2211023
548.
Koren MJ, et al. Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat. Med. 2022;28:96-103.
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549.
Khan, R. S. & Frishman, W. H. Zilebesiran: a promising antihypertensive therapy inhibiting angiotensinogen synthesis. Cardiol. Rev. 10.1097/CRD.0000000000000645 (2024).
Not in our library10.1097/crd.0000000000000645
550.
Desai AS, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N. Engl. J. Med. 2023;389:228-238.
Not in our library10.1056/nejmoa2208391
551.
Bakris GL, et al. RNA interference with zilebesiran for mild to moderate hypertension: the KARDIA-1 randomized clinical trial. JAMA. 2024;331:740-749.
Not in our library10.1001/jama.2024.0728
552.
Szabo GT, Mahiny AJ, Vlatkovic I. COVID-19 mRNA vaccines: platforms and current developments. Mol. Ther. 2022;30:1850-1868.
Not in our library10.1016/j.ymthe.2022.02.016
553.
Advances in COVID-19 mRNA vaccine development · 2022
No notice
554.
Baden LR, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 2021;384:403-416.
Not in our library10.1056/nejmoa2035389
555.
Polack FP, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 2020;383:2603-2615.
Not in our library10.1056/nejmoa2034577
556.
Grudda T, et al. Integrated hepatitis B virus DNA maintains surface antigen production during antiviral treatment. J. Clin. Investig. 2022;132:e161818.
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557.
Mak LY, et al. Bepirovirsen (GSK3228836) in chronic hepatitis B infection: an evaluation of phase II progress. Expert Opin. Investig. Drugs. 2023;32:971-983.
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558.
Yuen M-F, et al. Efficacy and safety of bepirovirsen in chronic hepatitis b infection. N. Engl. J. Med. 2022;387:1957-1968.
Not in our library10.1056/nejmoa2210027
559.
Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial · 2021
No notice
560.
Yuen MF, et al. Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. Lancet Gastroenterol. Hepatol. 2023;8:790-802.
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561.
Gupta SV, et al. Clinical and preclinical single-dose pharmacokinetics of VIR-2218, an RNAi therapeutic targeting HBV infection. Drugs RD. 2021;21:455-465.
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562.
Soriano V. Hepatitis B gene therapy coming to age. AIDS Rev. 2018;20:125-127.
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563.
Jain S, Kaur J, Prasad S, Roy I. Nucleic acid therapeutics: a focus on the development of aptamers. Expert Opin. Drug Discov. 2021;16:255-274.
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564.
Sabir F, et al. DNA based and stimuli-responsive smart nanocarrier for diagnosis and treatment of cancer: applications and challenges. Cancers (Basel). 2021;13:3396.
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565.
Augustine R, et al. pH-responsive polypeptide-based smart nano-carriers for theranostic applications. Molecules. 2019;24:2961.
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566.
Dirin M, Winkler J. Influence of diverse chemical modifications on the ADME characteristics and toxicology of antisense oligonucleotides. Expert Opin. Biol. Ther. 2013;13:875-888.
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567.
Amantana A, et al. Pharmacokinetics, biodistribution, stability and toxicity of a cell-penetrating peptide-morpholino oligomer conjugate. Bioconjugate Chem. 2007;18:1325-1331.
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568.
Gao X, et al. The association of autophagy with polyethylenimine-induced cytotoxicity in nephritic and hepatic cell lines. Biomaterials. 2011;32:8613-8625.
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569.
Takakusa H, et al. Drug Metabolism and pharmacokinetics of antisense oligonucleotide therapeutics: typical profiles, evaluation approaches, and points to consider compared with small molecule drugs. Nucleic Acid Ther. 2023;33:83-94.
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570.
Hashida M. Role of pharmacokinetic consideration for the development of drug delivery systems: A historical overview. Adv. Drug Deliv. Rev. 2020;157:71-82.
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571.
Jiang R, et al. Factors influencing ADME properties of therapeutic antisense oligonucleotides: physicochemical characteristics and beyond. Curr. Drug Metab. 2023;24:536-552.
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572.
Bosgra S, et al. The pharmacokinetics of 2’-O-methyl phosphorothioate antisense oligonucleotides: experiences from developing exon skipping therapies for duchenne muscular dystrophy. Nucleic Acid Ther. 2019;29:305-322.
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581.
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588.
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599.
Jeffrey S, et al. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial. J. Clin. Oncol. 2024;42:LBA9512.
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600.
Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer · 2023
No notice
601.
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602.
Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial · 2022
No notice
603.
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609.
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610.
Hu X, et al. Human cytomegalovirus mRNA-1647 vaccine candidate elicits potent and broad neutralization and higher antibody-dependent cellular cytotoxicity responses than the gB/MF59 vaccine. J. Infect. Dis. 2024;230:455-466.
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611.
Zanardi TA, et al. Safety, pharmacokinetic, and pharmacodynamic evaluation of a 2’-(2-methoxyethyl)-d-ribose antisense oligonucleotide-triantenarry n-acetyl-galactosamine conjugate that targets the human transmembrane protease serine 6. J. Pharmacol. Exp. Ther. 2021;377:51-63.
Not in our library10.1124/jpet.120.000222
612.
Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for non-alcoholic fatty liver disease: emerging targets and drug candidates. Biomedicines. 2022;10:274.
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613.
Bujko K, et al. Signaling of the complement cleavage product anaphylatoxin C5a through C5aR (CD88) contributes to pharmacological hematopoietic stem cell mobilization. Stem Cell Rev. Rep. 2017;13:793-800.
Not in our library10.1007/s12015-017-9769-6

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