Endosomal escape and current obstacles in ionizable lipid nanoparticles mediated gene delivery: lessons from COVID-19 vaccines

During last pandemic of COVID-19, two vaccines based on ionizable lipid nanoparticles (ILNP) were developed for COVID-19 prevention: Pfizer/BioNTech Vaccine (BNT162b2) and Moderna Vaccine (mRNA-1273). The observed efficacy of these two vaccine formulations catalyzed a global intensification of scientific inquiry into the therapeutic potential of these ionizable lipids, driving research efforts aimed at developing novel agents for a diverse range of pathologies. Successful ILNP-based delivery requires both selection of a suitable ionizable lipid and elucidation of its endosomal escape mechanism. This review focuses current knowledge on lipid diversity, emphasizing the structural and functional attributes of ionizable lipids essential for endosomal escape. A detailed analysis of COVID-19 vaccine lipid components, correlating their physicochemical properties with cellular and humoral immune responses, and exploring their implications for therapeutic innovation. Finally, we evaluate current challenges and future directions in ILNP-based therapy development.