Next-generation mRNA vaccines: strategies to overcome stability challenges

Messenger RNA (mRNA) vaccines represent a paradigm shift in rapid vaccine development and pandemic preparedness, enabling unprecedented speed in antigen design and scalable, cell-free manufacturing. Despite proven clinical efficacy, widespread mRNA vaccine deployment remains critically constrained by fundamental molecular instability requiring ultra-cold chain storage. The chemical lability of the RNA phosphodiester backbone, 2'-hydroxyl-mediated transesterification, oxidative nucleobase damage, and lipid nanoparticle (LNP) structural vulnerabilities collectively limit long-term stability and the feasibility of global distribution. This review provides a mechanistic analysis of RNA hydrolysis, oxidative degradation, lipid peroxidation, PEG-lipid desorption, and freeze-thaw-induced nanoparticle aggregation, linking molecular instability to translational challenges in storage and supply chain logistics. We critically evaluate engineering strategies to enhance stability, including optimized LNP architectures, lyophilization with vitrifying excipients, antioxidant incorporation, lipid-polymer hybrid nanocarriers, hydrogel-based depots, self-amplifying mRNA (saRNA), and circular RNA (circRNA) constructs. Stability modeling, cold-chain risk analysis, and regulatory Chemistry, Manufacturing, and Controls (CMC) considerations are discussed to contextualize formulation robustness within real-world distribution systems. Advancing mRNA vaccines beyond ultra-cold dependence will require coordinated innovation in RNA engineering, delivery system optimization, and scalable manufacturing to enable thermostable, resilient, and globally deployable vaccine technologies.