Nanoparticles in the clinic: An update post COVID ‐19 vaccines

1Over the past 2 years, the nanomedicine landscape has evolved rapidly, driven by the worldwide clinical introduction of the Moderna and Pfizer‐BioNTech COVID‐19 lipid nanoparticle mRNA vaccines. Given this sudden expansion of nanoparticle use in the clinic, we are updating our “Nanoparticles in the Clinic” review and providing an update on the clinical landscape of nanomedicines. Our original review was published in 2016 and highlighted >25 approved nanomedicines and >45 unapproved nanoparticles that were being evaluated clinical trials. In 2019, our second review included three new nanoparticle approvals, added >75 new clinicals trials for the previously highlighted unapproved nanoparticles, and added >15 new nanoparticles that entered clinical trials. In this 2021 update, we provide a broad overview of the current clinical landscape by adding two nanoparticles that recently received Emergency Use Authorization (both in 2020), >30 new trials that have started for previously tabulated unapproved nanoparticles, and >35 new nanoparticle technologies (associated with >55 new trials) that have recently entered clinical trials.

2Over the past 2 years, the nanomedicine landscape has evolved rapidly, driven by the global need for new technologies to provide prophylactic and therapeutic approaches against the coronavirus disease 2019 (COVID‐19),,, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Of the technologies that have emerged to combat COVID‐19, lipid nanoparticles are the delivery vehicle used in the Moderna and Pfizer‐BioNTech COVID‐19 vaccines, both of which were granted Emergency Use Authorization in the United States in 2020.

3The Moderna vaccine, mRNA‐1273, is a lipid nanoparticle consisting of the ionizable cationic lipid SM‐102 (heptadecan‐9‐yl 8 ((2 hydroxyethyl) (6 oxo 6‐(undecyloxy) hexyl) amino) octanoate), DSPC (1,2‐distearoyl‐snglycero‐3 phosphocholine), cholesterol, and PEG‐DMG (1 monomethoxypolyethyleneglycol‐2,3‐dimyristylglycerol with polyethylene glycol). mRNA‐1273 was granted Emergency Use Authorization by the U.S. FDA on December 18th, 2020, based on a number of clinical trials, including one that demonstrated anti‐SARS‐CoV‐2 immune responses in participants without trial‐limiting safety concerns and another clinical trial with 30,420 participants that demonstrated 94.1% efficacy at preventing COVID‐19 illness. The Pfizer‐BioNTech vaccine, BNT162b2, is also a lipid nanoparticle and consists of the ionizable cationic lipid ALC‐0315 ((4‐hydroxybutyl)azanediyl)bis(hexane‐6,1‐diyl)bis(2‐hexyldecanoate), DSPC (1,2‐distearoyl‐sn‐glycero‐3‐phosphocholine), cholesterol, and PEG‐DMA (2 [(polyethylene glycol)‐2000]‐N,N‐ditetradecylacetamide). BNT162b2 was granted Emergency Use Authorization by the U.S. FDA on December 11th, 2020, based on a number of clinical trials, including one that demonstrated both safety and immunogenicity of BNT162b2, and another clinical trial with 43,548 participants that demonstrated BNT162b2 was 95% effective in preventing COVID‐19. Both lipid nanoparticle formulations are administered intramuscularly in two separate doses and are used to encapsulate mRNA that encodes for the SARS‐CoV‐2 spike glycoprotein, which mediates attachment to host cells and thus enables viral entry. By encoding for this spike glycoprotein, the host generates an immune response to the presented antigenic proteins; thus, a neutralizing antibody response against SARS‐CoV‐2 is generated. In both formulations, lipid nanoparticles enable delivery of the sensitive mRNA cargo into the cytoplasm, which has been the major obstacle in translation of mRNA technologies. By overcoming the challenges of intracellular delivery using lipid nanoparticles, antigen presentation could occur and the neutralizing antibody response against SARS‐CoV‐2 was achieved. Collectively, mRNA‐1273 and BNT162b2 are used in >35 countries with an estimated 3 billion (2 billion for BNT162b2 and 1 billion for mRNA‐1273) doses to be manufactured throughout 2021.

4Table 1 has been updated to list FDA/EMA approved injectable nanomedicines up to 2021, including the lipid nanoparticle mRNA vaccines against COVID‐19. Figures 1 and 2 highlight key aspects of these tabulated findings. Figure 1 shows the chronological approvals of nanoparticles based on particle type. Lipid‐based and inorganic nanoparticles comprise the majority of clinically‐approved nanoparticles. Interestingly, the first (1989) and most recent (2020) clinically approved/authorized particles highlight how lipid‐based nanoparticles, as a platform technology, enable controlled interactions between encapsulated therapeutics and complex microenvironments within patients. While the majority of lipid‐based nanoparticles are approved and clinically‐used for intravenous applications, lipid‐based nanoparticles are also used to protect sensitive cargos (e.g., mRNA) after manufacturing, during storage, and during intramuscular muscular injection and throughout their action within the host. Figure 2 shows the chronological approvals of nanoparticles based on indication, with the dominant applications being cancer, anemia, and imaging.

5In addition to this updated Table 1, we also report an update on the number of clinical trials for approved nanoparticles that have appeared since our previous two articles in 2016 and 2019,: Figure 3 shows the number of clinical trials for each of the approved nanoparticles (see Table S1 for detailed summary) from 2016 (red) to 2019 (blue) to 2021 (green). Of particular note, we observe: (i) an increase in the number of clinical trials for 21 of the 29 approved nanoparticles in Table 1 (excluding the newly‐added mRNA‐1723 and BNT162b2), and (ii) an increase in the total number of clinical trials for approved nanoparticles from 1220 (in 2016), to 1716 (in 2019), and to 1935 (in 2021). Together, this demonstrates the continued success of nanoparticles that are being introduced into the clinic and the continued investigation of already‐approved nanoparticles toward expanding or improving their clinical use.

6In our previous article, >60 different non‐approved nanoparticles were listed as active in >100 clinical trials. Here, we are updating the current clinical landscape for each of these clinically investigated nanoparticles (Table 2). In this update, >40 new trials have been added. Regarding previous clinical trials that were available before 2019, 11 have been updated to active status, 5 have been updated to recruiting status, 5 have been terminated, 8 have been updated to unknown status, 12 have been completed, 3 have been withdrawn, and 12 have posted results that are viewable on ClinicalTrials.gov (Table 2). Of particular note: (i) 10 new trials began for a mitoxantrone hydrochloride liposome, used for the treatment of various cancers, (ii) 11 new trials began for Sonazoid, which is a lipid‐encapsulated formulation of F‐butane for ultrasound imaging, and (iii) results have been posted for PNT2258, DCR‐MYC, SGT‐53, NK105, CRLX101, CRLX301, AuroLase, and Halaven. Table 2 provides a detailed tabulation of these recent updates.

7Since our 2019 article, >35 new nanoparticle technologies have begun clinical trials. Of these new additions, 28 are lipid‐based (25 of which are for mRNA‐based vaccines). The remaining new nanoparticle technologies are indicated for cancer treatment (two pure‐drug nanoparticles are being studied in five different clinical trials), imaging applications (three trials are investigating carbon nanoparticles for imaging lymph nodes), and non‐mRNA vaccines (three protein‐based nanoparticles are being investigated as vaccines). Table 3 summarizes these new additions.

8The transformative role of lipid nanoparticles as mRNA delivery vehicles for combating COVID‐19 and their tremendous global impact during 2020 and 2021 has ushered in an unprecedented period for nanoparticle therapeutics. To date, >30 nanoparticles have been used in various clinical applications (Table 1) and >20 of these continue to be developed, with chronologically increasing activity in clinical trials (Figure 3 and Table S1). Of the 60 unapproved nanoparticle technologies currently being investigated in clinical trials, >100 active trials exist with >40 being added in this update alone (Table 2). Finally, since our previous update in 2019, there has been a massive surge in clinical introduction of new nanoparticle technologies, dominated by lipid nanoparticles for mRNA delivery; over 35 new nanoparticle technologies have entered clinical trials since 2019 (Table 3). Considering these recent updates and the global impact of nanoparticles in the clinic, especially as it relates to combating COVID‐19, the field of nanoparticle drug delivery is entering a new phase, wherein their development,, manufacturing,, and clinical utility is just beginning to scratch the surface.

9Aaron Anselmo: Conceptualization; data curation; formal analysis; supervision; writing ‐ original draft; writing‐review & editing. Samir Mitragotri: Conceptualization; formal analysis; supervision; writing ‐ original draft; writing‐review & editing.