Spatiotemporal Regulation of Oxidative Stress by Redox Relays for Ischemia‐Reperfusion Injury Rescue

Abstract Effective therapeutic strategies for ischemiareperfusion injury (IRI) remain elusive. Targeting reactive oxygen species (ROS) provides a practical approach to mitigate tissue damage following reperfusion. However, antioxidant mediated management of IRI is greatly hampered by the inefficient scavenging caused by spatiotemporal heterogeneity of intracellular oxidative stress. Herein, a redox relay strategy is exploited and the ReMEDY (Rescue by Mitochondrial Enhancement and Oxidative Detoxifying) nanosystem is developed to regulate oxidative spatiotemporal heterogeneity. ReMEDY co‐loads the coenzyme Q analog idebenone (IDE) and the superoxide dismutase mimetic iron chlorin e6 (FeCe6) into human serum albumin and encapsulates it with a hyaluronic acid‐modified lipid shell. The redox relay of ReMEDY combines one‐electron transfer of FeCe6 with the quinone cycle of IDE, resulting in broad‐spectrum ROS detoxification by simultaneously scavenging the superoxide radical burst and subsequent oxidation products. Meanwhile, IDE targets and repairs dysfunctional mitochondria, thereby achieving spatial regulation of oxidative damage. ReMEDY preferentially accumulates in damaged kidneys and efficiently scavenges varying degrees of oxidation and inhibits ferroptosis, while significantly strengthening mitochondrial function, inhibiting apoptosis, and ensuring suppression of proinflammatory cytokines, thereby rescuing renal IRI. These findings highlight strategies to address redox heterogeneity in IRI, providing insights into the treatment of other oxidative stress‐related diseases.