pH‐Activatable Pre‐Nanozyme Mediated H2S Delivery for Endo‐Exogenous Regulation of Oxidative Stress in Acute Kidney Injury

Abstract Oxidative stress induced by excess reactive oxygen species (ROS) is a primary pathogenic cause of acute kidney injury (AKI). Development of an effective antioxidation system to mitigate oxidative stress for alleviating AKI remains to be investigated. This study presents the synthesis of an ultra‐small Platinum (Pt) sulfur cluster (Pt 5.65 S), which functions as a pH‐activatable prefabricated nanozyme (pre‐nanozyme). This pre‐nanozyme releases hydrogen sulfide (H 2 S) and transforms into a nanozyme (Ptzyme) that mimics various antioxidant enzymes, including superoxide dismutase and catalase, within the inflammatory microenvironment. Notably, the Pt 5.65 S pre‐nanozyme exhibits an endo‐exogenous synergy‐enhanced antioxidant therapeutic mechanism. The Ptzyme reduces oxidative damage and inflammation, while the released H 2 S gas promotes proneurogenesis by activating Nrf2 and upregulating the expression of antioxidant molecules and enzymes. Consequently, the Pt 5.65 S pre‐nanozyme shows cytoprotective effects against ROS/reactive nitrogen species (RNS)‐mediated damage at remarkably low doses, significantly improving treatment efficacy in mouse models of kidney ischemia‐reperfusion injury and cisplatin‐induced AKI. Based on these findings, the H 2 S‐generating pre‐nanozyme may represent a promising therapeutic strategy for mitigating inflammatory diseases such as AKI and others.