Current landscape of mRNA technologies and delivery systems for new modality therapeutics｜Institute of Cellular and Organismic Biology, Academia Sinica

The potential of mRNA technology was prominently demonstrated during the global COVID-19 pandemic, yet its future clinical applications still face numerous challenges. Therefore, the editors of the Journal of Biomedical Science have specially invited Dr. Han-Chung Wu, Distinguished Research Fellow, to write a review article that covers an in-depth overview of the latest advancements in mRNA technology for the design of vaccines and therapeutic drugs, as well as delivery systems. The article also explores the challenges and future perspectives in the field. The main topics include:

1. The development and Rise of mRNA Drugs: In recent years, breakthrough advancements in mRNA technology have driven the development of novel therapeutics, such as antibody-drug conjugates (ADCs), gene therapies, chimeric antigen receptor (CAR) T-cell therapies, CRISPR gene-editing therapies, messenger RNA (mRNA) therapies, small interfering RNA (RNAi), and antisense oligonucleotides (ASOs). In 2018, the first RNA-based drug, patisiran (Onpattro™), was approved by the U.S. Food and Drug Administration (FDA), marking a significant milestone for the field. Due to the wide-ranging potential and ease of production of mRNA drugs, numerous clinical trials are currently underway to evaluate the efficacy of mRNA drugs and vaccines.

2. Design and Storage of mRNA: This section explores three different types of mRNA that have been applied in the development of mRNA drugs, including non-replicating mRNAs (nrRNAs), self-amplified mRNAs (saRNAs), and circular RNAs (circRNAs). On the other hand, mRNA-LNP faces challenges in maintaining stability during storage and transportation, mainly due to chemical degradation caused by hydrolysis and oxidation reactions, leading to mRNA backbone cleavage and secondary structure changes. We discuss the storage and cold chain management of mRNA-LNP, with freeze-drying proposed as a potential solution to enhance stability, extend shelf life, and expand the range of storage temperatures.

3. Design of Novel Lipids for LNP Delivery Systems: Lipid nanoparticles (LNPs) have become effective carriers for delivering mRNA drugs, protecting mRNA from degradation and promoting cellular uptake. LNPs are typically composed of four lipid components: (1) cationic/ionizable lipids, (2) helper phospholipids, (3) polyethylene glycol (PEG)-lipids, and (4) cholesterol. The design of ionizable lipids is crucial for the delivery efficiency of LNPs. Their structural characteristics, such as amine cores, degradable ester linkers, and thioester tails, affect LNP stability, cellular uptake, and endosomal escape. Studies have found that multi-tailed lipids, unsaturated thioester tails, self-degradable structures, and ligand-modified ionizable lipids can significantly improve mRNA delivery efficiency and targeting.

4. Endosomal Escape of LNPs: Endosomal escape is a key factor determining the delivery efficiency of nucleic acid drugs. In addition to developing novel ionizable lipids, other strategies, such as replacing cholesterol with β-sitosterol, replacing neutral helper lipid DMG-PEG with negatively charged DMPE-PEG, and using helper lipids containing phosphatidylethanolamine (PE), can promote endosomal escape and enhance mRNA delivery efficiency.

5. Targeting Delivery of mRNA-LNPs: Targeting delivery can enhance the efficacy of mRNA drugs and reduce side effects. Ligand-mediated targeted delivery involves attaching targeting ligands, e.g., antibodies, peptides, aptamers, glycans, or small molecules, to the surface of LNPs to achieve delivery to specific cells or tissues. Studies have shown that targeting ligands can successfully deliver mRNA-LNPs to immune cells, tumor cells, and organs.

6. Conclusion and Perspective: mRNA technology provides a “Game Changer” platform for drug development. However, to fully realize its clinical potential, future research should focus on developing novel delivery systems, optimizing LNP composition and structure, and exploring more effective targeting strategies. These efforts could lead to safer and more efficient mRNA delivery, opening new horizons for the treatment of various diseases.

This paper was supported by Academia Sinica, co-authored by the team of Distinguished Research Fellow, Han-Chung Wu, from the Institute of Cellular and Organismic Biology and the team of Research Fellow, Wen-Shan Li, from the Institute of Chemistry. The first author is Assistant Research Scientist, Rui-Min Lu, from the Biomedical Translation Research Center.