Lung-Specific mRNA Delivery by Ionizable Lipids with Defined Structure-Function Relationship and Unique Protein Corona Feature.

ABSTRACT: Targeted delivery of mRNA with lipid nanoparticles (LNPs) holds great potential for treating pulmonary diseases. However, the lack of rational design principles for efficient lung-homing lipids hinders the prevalence of mRNA therapeutics in this organ. Herein, the combinatorial screening with structure-function analysis is applied to rationalize the design strategy for nonpermanently charged lung-targeted ionizable lipids. It is discovered that lipids carrying N-methyl and secondary amine groups in the heads, and three tails originated from epoxyalkanes, exhibiting superior pulmonary selectivity and efficiency. Representative ionizable lipids with systematically variation in chemical structures are selected to study the well-known but still puzzling "protein corona" adsorbed on the surface

SUBMITTER: He X 

PROVIDER: S-EPMC11984862 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature