Reducing Complexity in Lipid Nanoparticles: Three-Component Zwitterionic Amino Lipids for Targeted Extrahepatic mRNA Delivery.

Simplicity and chemical expansion of lipid nanoparticles (LNPs) offer the potential for increased therapeutic benefit of mRNA vaccines and medicines. 3-Component Zwitterionic Amino Lipid (ZAL) LNPs offer simplicity and varied organ target scope, though there is a lack of chemical and formulation exploration with this class of lipids. Herein, we report the synthesis and evaluation of ZALs with improved biocompatibility, enhanced mRNA delivery efficacy, and extrahepatic organ-specific delivery through derivation at the secondary hydroxyl position with opivalate, chloride, bromide, and acetate. Evaluation of these novel ZAL molecules revealed organ-specific delivery trends, changes in delivery efficacy, and an engineering framework for chemically modifying lipid components that correlate with each specific chemical modification. Furthermore, the most efficacious ZAL derivative, which contains an acetate modification, displayed enhanced immune cell transfection in an organ-specific manner. This study provides a roadmap for reducing the complexity of LNPs by decreasing the number of lipid components in an LNP from the canonical 4 lipids to 3 lipids and expands the chemical scope of LNPs capable of mediating extrahepatic delivery.