Engineering Lipid Nanoparticles Beyond ApoE-Mediated Liver Tropism: Design Strategies for Extrahepatic and Organ-Selective Delivery

Lipid nanoparticles (LNPs) have evolved into a significant delivery technology for nucleic acid therapies, including messenger RNA (mRNA), small interfering RNA (siRNA), and genome editing tools. Although LNPs have demonstrated therapeutic success, they display strong tropism to the liver when systemically delivered, thus restricting their use for targeted delivery to extrahepatic organs. The major factor responsible for the liver targeting of LNPs is the binding of apolipoprotein E (ApoE) to the nanoparticle surface, which enables their recognition by lipoprotein receptors and uptake by liver cells. However, increasing evidence suggests that the tropism of LNPs can be altered by controlling lipid composition, physical and chemical properties, and acquired biological properties. This review discusses the mechanisms responsible for the liver tropism of LNPs as well as recent trends in modulating LNP tropism to extrahepatic organs. How ionizable lipids, helper lipids and sterols, PEG-lipids, LNP properties, and interaction with the protein corona can impact the organ tropism of LNPs as well as approaches for active and endogenous targeting of LNPs for organ- and cell-specific delivery are discussed. The challenges associated with organ- and cell-selective delivery of nucleic acids, such as delivery to functionally specific cell populations, endosomal release, species-specific translation, safety, repeated dosing, and clinical translation, are also described.