A celastrol derivative-based multifunctional nanozyme for oxidative stress scavenging and lipid metabolism regulation in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive hepatic lipid accumulation accompanied by persistent oxidative stress, posing a major challenge for effective therapeutic intervention. Here, we report a multifunctional nanozyme-based therapeutic platform, MIL@Cel-6-10/ASGR1 (MCA), designed to simultaneously address this issue through coordinated hepatocyte targeting, reactive oxygen species (ROS) scavenging, and lipid metabolism regulation. MCA is constructed from a Fe/Cu-based MIL-NH2 metal-organic framework (MOF) with intrinsic superoxide dismutase- and catalase-like activities, encapsulating a rationally engineered Celastrol derivative (Cel-6-10) for enhanced anti-inflammatory efficacy and stability. Surface conjugation an anti-asialoglycoprotein receptor 1 (ASGR1) monoclonal antibody confers hepatocyte-targeting capability and simultaneously activates liver X receptor alpha (LXRα), thereby promoting hepatic lipid efflux. In vitro, MCA effectively attenuates palmitate-induced hepatocyte lipotoxicity by reducing oxidative stress, suppressing apoptosis, and limiting lipid accumulation. In a diet-induced murine model of MASLD, MCA demonstrates pronounced liver accumulation, markedly ameliorates hepatic steatosis, improves serum lipid profiles, and reduces liver injury markers without detectable systemic toxicity. Transcriptomic analysis reveals extensive hepatic reprogramming, characterized by suppression of pro-steatotic and pro-inflammatory pathways and enhancement of antioxidant and metabolic homeostatic programs. Collectively, this work presents a Celastrol derivative-integrated nanozyme strategy as an effective materials-based approach for MASLD management.