Balancing immune evasion and hepatocyte delivery: a hybrid liposomal platform for enhanced nanotherapy in non-alcoholic fatty liver disease.

The clinical translation of nanomedicine for non-alcoholic fatty liver disease (NAFLD) is frequently hindered by rapid hepatic clearance mediated by Kupffer cells, which are the predominant phagocytic macrophages in the liver. Conventional stealth strategies, such as PEGylation, protect host cells from phagocytosis; however, their exploitation in drug delivery is limited by the prevailing assumption that immune evasion impairs cellular uptake. Our previous study demonstrated that liposomes functionalized with a CD47-derived self-peptide (SLip) effectively evaded macrophage clearance while retaining strong interactions with non-macrophage liver cells. Leveraging the decoupling of immune evasion and cellular accessibility, we developed a mixed liposomal system (MLip) composed of conventional liposomes (Lip) and SLip at tunable ratios, which enabled modulation of macrophage uptake. By adjusting the Lip:SLip composition, phagocytic efficiency was dose-dependently regulated, as confirmed by phagocytosis index assays. In vivo, MLip exhibited prolonged hepatic retention owing to delayed Kupffer cell clearance and enhanced delivery to hepatocytes and other parenchymal liver cells. To assess its therapeutic potential, silibinin was encapsulated within MLip, and collagenase I was surface-absorbed to promote extracellular matrix remodeling (ECM). Notably, the optimized 1:1 Lip/SLip formulation significantly attenuated liver fibrosis and improved histopathological outcomes in Lep ob/ob mice. This study presents a rational strategy to balance immune evasion with target cell engagement through hybrid liposomal engineering, offering a versatile and effective platform for liver-targeted nanotherapeutics with improved pharmacokinetics and therapeutic efficacy in NAFLD.