Chemotaxis-guided nanoplatform for non-alcoholic steatohepatitis therapy via macrophage reprogramming,...

Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis, has become a growing global health burden. Obeticholic acid (OCA, a farnesoid X receptor agonist) has shown limited efficacy due to poor solubility, single-target mechanisms, and off-target side effects, notwithstanding the great promise of this agent in NASH clinical trials. Here, we designed M2 macrophage-derived membrane (M2M)-camouflaged poly (lactic-co-glycolic acid) (PLGA) nanoparticles (O@PLGA@M) to achieve targeted OCA delivery to the inflamed liver niche for recovering hepatic homeostasis in NASH. The M2M improved the inflamed liver-targeting of the nanoplatforms via chemotaxis and promoted M1-to-M2 macrophage repolarization, as evidenced by a 2.5-fold increase in CD206 expression and 45 % reduction in CD86 expression in the liver. In a methionine/choline-deficient (MCD) diet-induced murine NASH model, O@PLGA@M exhibited excellent biosafety and multifaceted anti-NASH efficacy, including anti-steatosis, anti-inflammatory, and anti-fibrotic effects. Mechanistically, O@PLGA@M reprogrammed macrophages by modulating macrophage polarization and inhibiting recruitment of immune cells to reduce the inflammatory cascade. They also exerted hepatoprotection effects by reducing steatosis and hepatocyte damage. Moreover, O@PLGA@M modulated the gut microbiome by redirecting it towards a beneficial state, which further relieved NASH through the gut-liver axis. These findings demonstrated that the biomimetic nanoplatforms could be employed as promising strategies that integrated targeted delivery and multimodal synergistic therapy for NASH management.