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 of LNPs. In addition to the commonly used corona‐biomarker vitronectin, other arginine‐glycine‐aspartic acid (RGD)‐rich proteins usually involved in collagen‐containing extracellular matrix, such as fibrinogen and fibronectin have also been identified to have a strong correlation with lung tropism. This work provides insight into the rational design of lung‐targeting ionizable lipids and reveals a previously unreported potential function of RGD‐rich proteins in the protein corona of lung‐homing LNPs.