ROS-responsive diselenide exosomes restore mitophagy to resolve sterile inflammation in liver IRI

• Novel therapeutic platform: Developed bioengineered curcumin-loaded exosomes (Curcumin@EV) derived from mesenchymal stem cells for targeted liver therapy. • Mechanistic insight: Identified Mst1-PINK1 axis and cGAS-STING pathway as central drivers of mitochondrial dysfunction and inflammation in liver ischemia-reperfusion injury (IRI). • Dual-action protection: Curcumin@EV restores mitophagy (↓Mst1 → ↑PINK1/Parkin), reduces mitochondrial DNA leakage, and suppresses cGAS-STING–mediated inflammation. • Enhanced efficacy: Curcumin@EV outperforms free curcumin or exosomes alone in reducing apoptosis, oxidative stress (↓ROS), and promoting tissue regeneration (↑Ki-67, ↑CD31). • Clinical potential: Demonstrates biocompatibility and significant alleviation of liver IRI in vivo, supporting translational applications in transplantation and hepatic surgery. Liver ischemia–reperfusion injury (IRI) drives graft dysfunction and postsurgical morbidity. We show that hepatocellular MST1 is markedly upregulated in IRI and exacerbates damage by blocking PINK1-dependent mitophagy. Defective mitochondrial clearance causes mtDNA leakage, which activates macrophage cGAS–STING signaling and fuels inflammatory injury. Curcumin inhibits this MST1–PINK1 axis, restoring mitophagy and limiting mtDNA release. To translate these insights, we engineered Curcumin@EV@Se—stem-cell–derived extracellular vesicles surface-modified with diselenide-PEG for ROS-responsive, “stealth” delivery. In oxygen–glucose deprivation/reoxygenation models, Curcumin@EV@Se improved hepatocyte viability, preserved mitochondrial potential, reduced ROS and inflammatory cytokines, and promoted reparative/angiogenic programs. In a murine hepatic IRI model, systemic Curcumin@EV@Se decreased necrosis and TUNEL positivity and improved serum transaminases and histology, indicating enhanced liver function and regeneration. These data identify MST1-mediated mitophagy blockade with secondary cGAS–STING activation as a central pathogenic axis in IRI and present Curcumin@EV@Se as a mechanism-guided therapy that restores mitochondrial quality control and dampens innate immune activation, with translational promise for liver transplantation and acute hepatic injury. Production pathway and therapeutic mechanism of Curcumin@EV@Se.