Overcoming hepatic tropism: Precision engineering of lipid nanoparticles for extrahepatic RNA delivery

Lipid nanoparticles (LNPs) are effective carriers for RNA and have become the standard of care; however, their natural affinity for the liver restricts their use elsewhere. To address this limitation, the "biological identity" of LNPs must be reprogrammed by modifying the three interconnected factors of lipid composition, physicochemical properties and protein corona modulation. Many previous studies have tended to evaluate individual regulatory factors in isolation; therefore, building on prior research, this review establishes a comprehensive conceptual framework that integrates these three dimensions to systematically elucidate the design principles for achieving extrahepatic targeting of LNPs. Targeting strategies are classified according to the mechanism of organ accumulation: (1) Endogenous corona-mediated (SORT, ENDO, POST), these approaches are independent of direct exogenous ligand-receptor interactions and rely on the recruitment of specific plasma proteins; within this category, POST is further distinguished by peptide-remodeled coronas; (2) Covalent active targeting - surface-conjugated ligands that directly bind to cell-surface receptors; and (3) Passive accumulation - regulated by vascular permeability. This review summarizes recent advances in delivery to the lungs, spleen, brain, heart, kidney, bone, and pancreas, discusses major translational bottlenecks (species differences, immunogenicity, and manufacturing), and proposes a direction for predictive design.