Regio-divergent strategy inspired construction of ionizable lipidoids enable high performance in mRNA delivery

Ionizable lipidoids show high delivery efficiency and tunable organ selectivity in the lipid nanoparticle (LNP) platform, but limited substrate options constrain their structural variety and performance. This study presents a regio-divergent strategy combining ring-opening and Michael addition reactions of diamines to construct a preliminary library of fifteen ionizable lipidoids from three starting materials: diamine, acrylate, and epoxide. Within this library, scaffold 3T2 exhibited excellent delivery efficiency. Further linker and hydrophobic tail optimization led to E16N4Ac18, which showed spleen-targeting after systemic administration. Inhalation delivery of mRNA@E16N4Ac18-LNPs achieved a 2.4-fold higher transfection efficiency than commercial SM-102. This regio-divergent approach offers a conceptual and practical framework for mRNA delivery lipidoid design.