A dual-responsive CO-releasing nanogel ameliorates retinal ischemia-reperfusion injury by restoring mitochondrial homeostasis and attenuating cGAS-STING pathway activation.

Retinal ischemia-reperfusion injury (RIRI) represents a central pathological mechanism underlying neurodegeneration in multiple blinding ocular diseases, including glaucoma, diabetic retinopathy, and retinal vein occlusion. Ischemic stress triggers a surge of reactive oxygen species (ROS) within retinal ganglion cells, leading to mitochondrial dysfunction and initiating a vicious cycle of cellular damage. Targeting the regulation of redox balance within the RIRI microenvironment to restore mitochondrial homeostasis remains a major challenge in RIRI therapy. Here, a dual ROS-responsive carbon monoxide (CO) prodrug nanoplatform (COPN) was developed. This system integrates a ROS-sensitive CO-releasing molecule, CORM401, as the active prodrug unit, which is encapsulated within a disulfide-crosslinked dendritic nanogel matrix, thereby enabling site-specific CO release under pathological oxidative conditions. Locally released CO effectively neutralizes excessive ROS, restores mitochondrial quality control, and prevents mitochondrial DNA cytosolic leakage, thereby attenuating cGAS-STING pathway activation and subsequent neuroinflammatory responses. Furthermore, COPN successfully reverses ischemia-induced immunometabolic dysregulation, restores oxidative phosphorylation capacity, and enhances cellular metabolic resilience. This study offers a promising therapeutic strategy with strong translational potential for treating oxidative retinal diseases.