A multifunctional MOF-818-based nanozyme for synergistic therapy of hepatic steatosis via dual-channel lipid regulation and ROS scavenging

The treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) remains a major clinical challenge due to its complex pathogenesis, which involves dysregulated lipid metabolism and severe oxidative stress. To address this issue, we produced a novel and multifunctional nanozyme, MOF-818@UDPG/ASGR1, designed for synergistic therapy via dual-channel lipid regulation and potent reactive oxygen species (ROS) scavenging. The nanozyme was synthesized by functionalizing a trinuclear copper-based MOF-818 core, possessing intrinsic superoxide dismutase (SOD) and catalase (CAT) activities, with uridine diphosphate glucose (UDPG) and an asialoglycoprotein receptor 1 (ASGR1) antibody. The surface-conjugated ASGR1 antibody not only facilitated specific hepatocyte targeting but also triggered intracellular signaling pathways, activated liver X receptor α (LXRα), and promoted cholesterol and lipid efflux. Concurrently, the encapsulated UDPG was delivered intracellularly to the Golgi apparatus, where it could bind to and induce the degradation of site-1 protease (S1P), effectively blocking the proteolytic activation of the key lipogenic transcription factor SREBP1c and suppressing de novo lipogenesis. In both cellular and diet-induced murine models of MASLD, MOF-818@UDPG/ASGR1 showed superior efficacy in alleviating hepatic steatosis, reducing oxidative damage, improving serum lipid profile, restoring liver function (ALT/AST), and protecting against hepatocyte apoptosis. Transcriptomic (RNA-seq) and molecular analyses also validated the coordinated activation of LXRα and suppression of SREBP1c, confirming the proposed synergistic mechanism. This study presents a powerful and rationally designed nano-therapeutic strategy that addresses multiple pathological axes in MASLD, offering a promising and integrated treatment approach.