Cell Membrane-Coated Nanoparticles Against Non-Alcoholic Fatty Liver Disease via Regulating Endoplasmic Reticulum Stress

Abstract Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health challenge, yet the available therapeutic options remain limited. Evidence suggests that NAFLD may advance to more serious conditions, including steatohepatitis or cirrhosis, which are associated with poor outcomes. Current drug therapies exhibit insufficient therapeutic efficacy due to short half-life and premature clearance. In this work, we elucidate the critical impact of endoplasmic reticulum stress (ERS) on inflammatory process associated with NAFLD using bioinformatics tools. By analyzing single-cell RNA sequencing data from an animal model of NAFLD, we identified hepatocytes as the primary cell type implicated in ERS. Melatonin (Mel), a compound known for its antioxidative properties, also modulates the ERS pathway, suggesting its potential to slow NAFLD progression. To exploit this therapeutic potential, we developed a nanoparticle, GalNAc-MM@PLGA/Mel, which incorporates engineered macrophage membranes to specifically target hepatocytes and mitigate ERS. The addition of GalNAc moieties on the membrane significantly enhanced the ability of nanoparticles to specifically bind to hepatocytes. Moreover, Melatonin, delivered through this platform, effectively reduced inflammation and lipid accumulation by inhibiting both the ERS pathway and its downstream NF-κB signaling cascade. Consequently, this engineered nanoparticle-based strategy offers a promising, safe, and cost-efficient approach to managing NAFLD.