Couture-Senecal, J.; Tilstra, G.; Khan, O. F.

The optimization of lipid nanoparticles (LNPs) has played a key role in enhancing the efficacy of mRNA vaccines, yet challenges with LNP tolerability remain. The ionizable lipid component within LNPs is critical to the efficient delivery of mRNA. Ionizable lipids can also trigger innate immune activation, which is beneficial for vaccine efficacy but may contribute to adverse inflammatory reactions. Engineering ionizable lipids for rapid biodegradation is a promising, yet underexplored, strategy to dampen inflammation. Here, we report the rational design and optimization of biodegradable ionizable lipids for intramuscular mRNA vaccines in mice. We show that in vivo biodegradability is enhanced by controlling lipid hydrolysis kinetics and that protein output is maximized by tuning the LNP apparent pKa. In an influenza vaccine model, the lead lipid ({delta}O3) generates equivalent neutralizing antibodies and stronger antigen-specific T cell responses compared to a benchmark lipid (SM-102) used in approved mRNA vaccines. Furthermore, by comparing ionizable lipid analogs with similar potency but opposing biodegradation kinetics, we find that faster lipid clearance from tissues coincides with a lower inflammatory response while preserving strong vaccine immunogenicity. These findings demonstrate that fast-degrading ionizable lipids can balance the efficacy and tolerability of mRNA vaccines, with implications for addressing side effects and patient acceptance of new vaccine applications.