Messenger RNA (mRNA) is a type of RNA that carries genetic information from DNA to the ribosome, where it is translated into proteins. mRNA has emerged as a powerful platform for development of new types of medicine, especially after the clinical approval of COVID-19 mRNA vaccines. Chemical modification and nanoparticle delivery have contributed to this success significantly by improving mRNA stability, reducing its immunogenicity, protecting it from enzymatic degradation, and enhancing cellular uptake and endosomal escape. Recently, substantial progresses have been made in new modification chemistries, sequence design, and structural engineering to generate more stable and efficient next-generation mRNAs. These innovations could further facilitate the clinical translation of mRNA therapies and vaccines. Given that numerous review articles have been published on mRNA nanoparticle delivery and biomedical applications over the last few years, we herein focus on overviewing recent advances in mRNA chemical modification, mRNA sequence optimization, and mRNA engineering (e.g., circular RNA and multitailed mRNA), with the aim of providing new perspectives on the development of more effective and safer mRNA medicines.

As an attractive alternative to plasmid DNA, messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapeutics for biomedical applications. Advances in addressing the inherent shortcomings of mRNA and in the development of nanoparticle-based delivery systems have prompted the development and clinical translation of mRNA-based medicines. In this review, we discuss the chemical modification strategies of mRNA to improve its stability, minimize immune responses, and enhance translational efficacy. We also highlight recent progress in nanoparticle-based mRNA delivery. Considerable attention is given to the increasingly widespread applications of mRNA nanomedicine in the biomedical fields of vaccination, protein-replacement therapy, gene editing, and cellular reprogramming and engineering.