The stability landscape of mRNA vaccines: challenges and mitigation strategies

mRNA vaccines have emerged as a transformative platform in vaccinology, offering rapid development, high immunogenicity, and flexible design for preventing infectious diseases and treating various medical conditions. However, their widespread application is significantly hampered by inherent stability challenges, including molecular degradation, stringent cold-chain requirements, and limited shelf life. This review systematically examines the multidimensional factors influencing mRNA vaccine stability, encompassing molecular-level vulnerabilities of mRNA (such as hydrolysis-prone sites and nuclease sensitivity), structural and compositional stability of lipid nanoparticles (LNPs) delivery systems, and external environmental stressors (temperature, pH, nucleases). Crucially, we highlight innovative strategies to overcome these limitations, including molecular engineering of mRNA (5' cap analogs, optimized UTRs, elongated poly(A) tails, and nucleotide modifications), advanced LNP design (tunable ionizable lipids, PEGylation, and biocompatible formulations), and the application of lyophilization (freeze-drying) technology for ambient temperature storage. By integrating insights from recent advances in RNA biology, nanotechnology, and pharmaceutical engineering, this review provides a comprehensive framework for developing next-generation mRNA vaccines with enhanced stability, eliminated cold-chain dependence, and improved global accessibility-paving the way for broader clinical translation and equitable vaccine distribution.