The emergence of mRNA vaccines has heralded an epoch in disease prevention and treatment. Safe and efficient mRNA delivery systems are highly desired for the widespread application of mRNA therapeutics. Herein, we have designed a facile synthetic pathway for producing ionizable lipids featuring various branched linkers. These lipids have been integrated into lipid nanoparticles (LNPs) to improve the delivery of mRNA vaccines. The influence of linker structure on lipids and LNPs is currently underreported, yet it undeniably exerts a substantial impact on the outcomes. Through systematic screening and formulation optimization, we have identified that LNPs comprising ionizable lipids with a branched β-isobutylglutarate linker (bLNPs) exhibited superior transfection capabilities. In preclinical cancer prevention and treatment models, mRNA vaccines delivered by bLNPs (mRNA-bLNPs) have shown significant efficacy without causing systemic toxicity, highlighting the potential of bLNPs for clinical translation. Our synthetic strategy facilitates the expansion of the LNP library and provides valuable insights into the relationship between linker structures and delivery efficiency, thereby propelling the advancement of LNP technology.
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