Targeted hepatic delivery of ezetimibe via red blood cell-coated nanoparticles for the treatment of non-alcoholic fatty liver disease through inflammation modulation.

This study investigates the potential of red blood cell (RBC) membrane-coated, ezetimibe-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles for targeted therapy of non-alcoholic fatty liver disease (NAFLD). PLGA nanoparticles were fabricated and subsequently camouflaged with RBC membranes to enhance hepatic targeting. The nanoparticles were characterized for size, surface potential, and encapsulation efficiency. Physicochemical characterization revealed increased particle size upon membrane coating (PLGA: 221.2 ± 26.0 nm; RBC-PLGA: 255.2 ± 14.1 nm), corroborated by transmission electron microscopy. In vitro release kinetics were systematically evaluated, showing sustained drug release for both formulations. Biodistribution studies in rats demonstrated predominant hepatic accumulation of both nanoparticles, with higher liver deposition observed for RBC-PLGA (106.43 ± 40.08 µg) compared to uncoated PLGA nanoparticles (101.41 ± 34.15 µg). In vivo efficacy was assessed in a high-fat diet-induced NAFLD rat model. All ezetimibe-treated groups exhibited significant reductions in serum cholesterol levels, hepatic lipid accumulation, and liver enzyme activities. Metabolomics and lipidomics analyses further revealed that RBC-PLGA nanoparticles induced the most pronounced alterations in hepatic metabolic and lipid profiles. Moreover, studies demonstrated route-dependent modulation of key proteins implicated in NAFLD pathogenesis. Collectively, these findings suggest that RBC membrane-coated nanoparticles significantly enhance the liver-specific delivery and therapeutic efficacy of ezetimibe in NAFLD, while offering mechanistic insights into metabolic and lipidomic modulation associated with different administration routes.