Progress and prospects of mRNA-based drugs in pre-clinical and clinical applications

Abstract

In the last decade, messenger ribonucleic acid (mRNA)-based drugs have gained great interest in both immunotherapy and non-immunogenic applications. This surge in interest can be largely attributed to the demonstration of distinct advantages offered by various mRNA molecules, alongside the rapid advancements in nucleic acid delivery systems. It is noteworthy that the immunogenicity of mRNA drugs presents a double-edged sword. In the context of immunotherapy, extra supplementation of adjuvant is generally required for induction of robust immune responses. Conversely, in non-immunotherapeutic scenarios, immune activation is unwanted considering the host tolerability and high expression demand for mRNA-encoded functional proteins. Herein, mainly focused on the linear non-replicating mRNA, we overview the preclinical and clinical progress and prospects of mRNA medicines encompassing vaccines and other therapeutics. We also highlight the importance of focusing on the host-specific variations, including age, gender, pathological condition, and concurrent medication of individual patient, for maximized efficacy and safety upon mRNA administration. Furthermore, we deliberate on the potential challenges that mRNA drugs may encounter in the realm of disease treatment, the current endeavors of improvement, as well as the application prospects for future advancements. Overall, this review aims to present a comprehensive understanding of mRNA-based therapies while illuminating the prospective development and clinical application of mRNA drugs.

Fig. 1

Chronological development of mRNA drugs. Yellow box, common events of mRNA drugs; green box, mRNA-based non-immunotherapy; red box, mRNA-based immunotherapy. From 1961 to 1990: mRNA discovery and the maturation of IVT mRNA technology, including the discovery of mRNA, purified mRNA could be translated into proteins in the mammalian cell-free system, discovery of mRNA cap, discovery of single-stranded circular RNA, cap analog commercialized, synthetic mRNA was first produced in the laboratory by IVT, T7 RNA polymerases commercialized. From 1990 to 2019: the exploration of mRNA vaccines, particularly for cancer therapy, including IVT mRNA injected into the mouse skeletal muscle achieved protein translation, vasopressin mRNA injected into the hypothalamus of Brattleboro rats was found to successfully express vasopressin, mRNA vaccine encoding tumor antigen in mice, first clinical trial of mRNA-engineered DCs vaccine strategy,^– first DC vaccine with autologous tumor mRNA was used to treat clinical Phase I/II of advanced malignant melanoma trial (NCT01278940),^, first attempt was made to inject an mRNA vaccine directly into humans to fight tumors (NCT00204607),^, nucleotide-modified RNA reduced the potential for immune stimulation, first personalized cancer mRNA vaccine in clinical trial (NCT02035956),^, first clinical trial of prophylactic mRNA vaccine (CV7201) against rabies (NCT02241135), NIH called for gender to be included in biological variables in preclinical and clinical studies, first mRNA (AZD8601) therapy encoding VEGF-A to enter the clinic (NCT02935712), first clinical trial of mRNA-encoding immunostimulant (mRNA-2416, NCT03323398). From 2019 to the present: rapid development of mRNA-based therapeutics, including two mRNA vaccines (mRNA-1273 and BNT162b2) have been approved for emergency use by the FDA,^, first to use unmodified mRNA in regenerative medicine, forty-three COVID-19 mRNA vaccines were in clinical trials, first combining mRNA therapy with photodynamic therapy to fight tumors, Phase III trial of mRNA-4157 plus Pembrolizumab in the treatment of melanoma. IVT in vitro transcription, NIH the National Institutes of Health, DCs dendritic cells, FDA the Food and Drug Administration. The graphic is created with Adobe Illustrator

Fig. 2

mRNA codes for immunotherapy-associated antigen, antibody, cytokine, ligand, tumor suppressor protein, and adoptive cell therapy. RV rotavirus, VZV varicella-zoster virus, RSV respiratory syncytial virus, CMV cytomegalovirus, HPV human papillomavirus, EBV Epstein–Barr virus, RABV rabies virus, HIV human immunodeficiency virus, MPXV monkeypox virus, anti-VEGF anti-vascular endothelial growth factor. The graphic is created with BioRender.com

Fig. 3

Application of mRNA vaccine in immunotherapy. a Types of COVID-19 vaccines in clinical trials (from WHO; March 30, 2023). b mRNA-based drugs in Phase III/IV trials. On clinicaltrial.gov, search for “mRNA” as the only keyword and the search criteria are limited to “Phase 3” and “Phase 4”. Note that this search method cannot find all mRNA vaccines, and some mRNA vaccines do not contain the word “mRNA”, so the figure should be viewed dialectically. PS protein subunit, VVnr viral vector (non-replicating), IV inactivated virus, VVr viral vector (replicating), VLP virus-like particle, VVr + APC VVr + antigen-presenting cell, LAV live attenuated virus, VVnr + APC VVnr + antigen-presenting cell, BacAg-SpV bacterial antigen-spore expression vector

Fig. 4

Overview diagram of mRNA-based non-immunotherapy. BDNF brain-derived neurotrophic factor, NEP neprilysin, CFTR cystic fibrosis transmembrane conductance regulator, HNF4A human hepatocyte nuclear factor α, COL1A1 extracellular-matrix α1 type-I collagen, VEGF-A vascular endothelial growth factor-A, TE tropoelastin, BMP-2 bone morphogenetic protein-2, RUNX1 runt-related transcription factor 1, OTC ornithine transcarbamylase, G6Pase-α glucose-6-phosphatase-alpha, AGL amylo-α-1,6-glucosidase 4-alpha-glucanotransferase, IGF-1 insulin-like growth factor 1, ZFNs Zinc finger nucleases, CRISPR/Cas9 clustered regularly interspaced short palindromic repeats/associated protein 9. The graphic is created with BioRender.com

Fig. 5

Immunization background map. The variations in individuals’ immunological backgrounds may serve as a potential mechanism for the diversity in vaccine efficacy and adverse reactions following mRNA vaccination. An individual’s immune background is shaped by a multitude of factors, encompassing both physiological conditions and pathological conditions. Moreover, it is crucial to consider the potential adverse effects of repeated or intensive vaccination using the same or multiple vaccines. The graphic is created with BioRender.com