Ze Zhang, Yenhui Ong, Bowei Yang, Bangda Fan, Yi Yan Yang, Qianqian Ni
The inception of mRNA vaccines for COVID-19 has catalyzed a transformative shift in the field of vaccination, offering expeditious, scalable, and potent countermeasures to a global health emergency. Despite significant advances, mRNA remains inherently unstable under physiological conditions due to its susceptibility to degradation by ubiquitous ribonucleases and physicochemical factors, making its storage, transport and clinical application challenging. This review explores the critical determinants influencing mRNA stability and discusses how chemical engineering strategies are suited to enhance mRNA stability, including 5' cap modification, poly(A) tail engineering, optimization of untranslated regions, as well as coding sequence refinements, reversible 2'-OH acylation, the development of circular RNA constructs and self-amplifying RNA systems. We also discuss efforts towards mRNA immunogenicity regulation and advanced mRNA delivery systems, along with progress in storage and transport solutions, which have further contributed to addressing stability concerns. Finally, we discuss the remaining challenges in clinical translation and provide forward-looking perspectives on emerging mRNA-based technologies.