An Integrated Nanozyme-Exosome Platform for Multi-Targeted Therapy of Metabolic-Associated Steatotic Liver Disease.

Metabolic-associated steatotic liver disease (MASLD) is a prevalent chronic liver disorder driven by a complex interplay of lipid accumulation, oxidative stress, and inflammation, for which effective targeted therapies remain limited. To address this multifactorial pathology, we developed an integrated nano-therapeutic platform, termed CMEPA, that unites three complementary components: a copper-based nanozyme with dual superoxide dismutase (SOD)- and catalase (CAT)-like activities, human umbilical cord mesenchymal stem cell-derived exosomes (UC-MSC-Exos) enriched in regulatory microRNAs, and a hepatocyte-targeting antibody against ASGR1. In vitro, CMEPA efficiently scavenged reactive oxygen species (ROS), significantly reduced lipid droplet accumulation, and suppressed apoptosis in palmitic acid-challenged hepatocytes. In vivo, CMEPA exhibited preferential hepatic accumulation and an excellent biosafety profile, with no observable systemic toxicity. Therapeutic evaluation in a diet-induced murine MASLD model revealed that CMEPA administration significantly improved serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride, and cholesterol levels, alleviated hepatic steatosis as confirmed by histopathology, enhanced endogenous SOD and CAT activities, and attenuated inflammatory and lipogenic signaling pathways, as revealed by transcriptomic analysis. Collectively, these results establish CMEPA as a robust, multi-modal nano-therapeutic strategy that integrates catalytic antioxidation, exosome-mediated gene regulation, and active hepatocyte targeting, offering a promising translational approach for MASLD treatment.