Thiol‐Disulfide Exchange Engineered BSA‐Derived Nanoprodrug for Precise Delivery of Hydropersulfides Against Hepatic Ischemia/Reperfusion Injury

ABSTRACT Hydropersulfides, noted for their potent reducing and nucleophilic characteristics, protect cells against severe oxidative damage. Nevertheless, the free hydropersulfides groups exhibit instability in blood circulation, potentially eliciting disproportionation reactions among themselves. To address this issue, a ROS‐responsive bovine serum albumin‐derived hydropersulfide nanomedicine (BSA‐SS‐PBAP NPs) was engineered by a thiol‐disulfide exchange strategy that employed BSA‐SH with multiple exposed thiol groups and phenylboronic acid pinacol ester‐SS‐pyridine (PBAP‐SS‐Py). Upon intravenous administration in ischemia/reperfusion‐induced acute liver injury (ALI) mice at 0 h post‐reperfusion, BSA‐SS‐PBAP NPs exhibited excellent colloidal stability in the blood circulation, rapidly targeted the damaged liver, and were internalized by hepatocytes. Under pathological conditions with elevated ROS levels, the responsively released hydropersulfides reshaped the redox equilibrium by eliminating free radicals, replenishing the thiol pool, and restoring the GSH/GSSG cycle, therefore reducing lipid peroxide accumulation. This process subsequently suppressed the Bcl‐2/Bax/Cyt‐C/cleaved caspase‐3/9/12 apoptotic pathways (apoptosis reduced by over 90%), thereby rescuing dying hepatocytes, alleviating the inflammatory cascade, and ultimately improving liver function (AST and ALT normalized within 12 h). The therapeutic administration, administered 3 h post‐reperfusion, emulated a clinical regimen and displayed comparable hepatoprotective benefits. This BSA‐derived hydropersulfides prodrug platform holds tremendous translational potential for ALI and other oxidative stress‐related disease therapies.