Ligand‐Mediated Reprogramming Redirects Liver‐Tropic Ionizable Lipid Nanoparticles for Lung‐Selective mRNA Delivery

ABSTRACT Systemic delivery of messenger RNA (mRNA) to target tissues and cells using lipid nanoparticles (LNPs) holds transformative potential for gene therapy. However, most clinically validated LNP exhibit strong liver tropism, and redirecting their organ specificity without redesigning entirely new chemistries remains challenging. Here we present a ligand‐mediated lipid reprogramming approach that repurposes chemically defined, liver‐tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver. From a library of 90 degradable lipidoids, we identified 2‐t6b as a potent liver‐targeting platform. By site‐specific displaying of small molecule ligands onto 2‐t6b headgroup, we engineered a series of reconfigured lipidoids that achieve lung‐specific targeting while retaining the parent delivery scaffold. Ligand7‐2‐t6b‐lipid‐functionalized LNP achieved over 200‐fold higher mRNA translation in the lungs compared to the parent liver‐tropic LNP. Proteomics and molecular docking analysis revealed enhanced binding of the modified lipid to vitronectin, a serum glycoprotein that improves integrin binding and thus promotes cellular uptake and translation efficiency. Ligand‐mediated 2‐t6b/ligand7 LNPs achieved outperformed efficacy and therapeutic potential in lung‐specific genome editing relative to SORT‐constructed 2‐t6b LNP system. Our modular reprogramming strategy provides a generalizable framework to upgrade existing liver‐biased LNPs into lung‐selective mRNA carriers, advancing next‐generation tissue‐specific mRNA therapies for gene editing, protein replacement therapy, and regenerative medicine.