The study aims to reformulate lipid nanoparticles (LNPs) to achieve simultaneous organ-specific accumulation and effective translation of mRNA. By adjusting the lipid structures and compositions, the researchers designed a combinatorial library of degradable-core based ionizable cationic lipids. This approach demonstrated that cholesterol and phospholipid are not essential for LNP functionality, and their removal addresses the challenge of preventing hepatic accumulation. The optimized LNP formulations, particularly the 3-Comp strategy (ionizable cationic lipid/permanently cationic lipid/PEG-lipid), showed superior pulmonary targeting without liver accumulation. These findings provide a promising approach for precise mRNA therapy, expanding its potential in treating a wide range of diseases.The study aims to reformulate lipid nanoparticles (LNPs) to achieve simultaneous organ-specific accumulation and effective translation of mRNA. By adjusting the lipid structures and compositions, the researchers designed a combinatorial library of degradable-core based ionizable cationic lipids. This approach demonstrated that cholesterol and phospholipid are not essential for LNP functionality, and their removal addresses the challenge of preventing hepatic accumulation. The optimized LNP formulations, particularly the 3-Comp strategy (ionizable cationic lipid/permanently cationic lipid/PEG-lipid), showed superior pulmonary targeting without liver accumulation. These findings provide a promising approach for precise mRNA therapy, expanding its potential in treating a wide range of diseases.