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

Abstract Nanoparticles are used in the clinic to treat cancer, resolve mineral deficiencies, image tissues, and facilitate vaccination. As a modular technology, nanoparticles combine diagnostic agents or therapeutics (e.g., elements, small molecules, biologics), synthetic materials (e.g., polymers), and biological molecules (e.g., antibodies, peptides, lipids). Leveraging these parameters, nanoparticles can be designed and tuned to navigate biological microenvironments, negotiate biological barriers, and deliver therapeutics or diagnostic agents to specific cells and tissues in the body. Recently, with the Emergency Use Authorization of the COVID‐19 lipid nanoparticle vaccines, the advantages and potential of nanoparticles as a delivery vehicle have been displayed at the forefront of biotechnology. Here, we provide a 5‐year status update on our original “Nanoparticles in the Clinic” review (also a 2‐year update on our second “Nanoparticles in the Clinic” review) by discussing recent nanoparticle delivery system approvals, highlighting new clinical trials, and providing an update on the previously highlighted clinical trials.


| INTRODUCTION
Over 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. 1 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. 2 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. 3 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.

| UPDATES ON CURRENTLY APPROVED NANOPARTICLES AND NEW ADDITIONS
Over 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), [4][5][6] which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 7 Of the technologies that T A B L E 1 Clinically approved nanoparticle therapies and diagnostics, grouped by their broad indication response to the presented antigenic proteins; thus, a neutralizing antibody response against SARS-CoV-2 is generated. 15 In both formulations, lipid nanoparticles enable delivery of the sensitive mRNA cargo into the cytoplasm, 16 which has been the major obstacle in translation of mRNA technologies. 17 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 10 with an estimated 3 billion (2 billion for BNT162b2 and 1 billion for mRNA-1273) doses to be manufactured throughout 2021. 18 Table 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.
In 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 2,3 : 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

| UPDATE ON PREVIOUS CLINICAL TRIALS FOR UNAPPROVED NANOPARTICLES
In our previous article, 3 >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 F I G U R E 3 Chronological update on the number of clinical trials for each nanoparticle, based on the number of identified trials in our previous "Nanoparticles in the Clinic" reviews in 2016 2 and 2019. 3 Table 3 summarizes these new additions.

| CONCLUSION
The 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 (