Biosponge‐Armored Nanodots Restore Redox‐Calcium Homeostasis to Mitigate Reperfusion‐Induced Injury in Ischemic Stroke

Abstract Antioxidant nanomaterials demonstrate significant neuroprotective potential in mitigating reperfusion injury associated with ischemic stroke. However, emerging nanocatalytic strategies targeting oxidative stress suffer from limited therapeutic efficacy owing to their reliance on singular mechanisms of action. In this study, ultrasmall iridium (Ir)‐based catalytic nanodots encapsulated in biopolymers (HIr‐PS) are developed to address ischemic stroke by concurrently normalizing redox and calcium homeostasis. The engineered HIr‐PS is found to possess multiple antioxidant enzyme‐mimetic activities and exhibits superior reactive oxygen species (ROS)‐scavenging efficacy compared to that of bare Ir and IrO 2 nanodots. Surface‐functionalized biopolymers act as sponges to selectively sequester excess intracellular calcium through coordination interactions. This dual function enables HIr‐PS to protect neuronal cells from oxidative stress, restore mitochondrial function, and alleviate endoplasmic reticulum stress. Consequently, HIr‐PS treatment promotes neuronal survival and remodels the pro‐inflammatory microenvironment, as validated in a mouse model of middle cerebral artery occlusion. Mechanistically, these effects are attributed to the abilities of HIr‐PS to penetrate the blood–brain barrier and disrupt the vicious loop of ROS overproduction and calcium overload. This study presents a distinct paradigm for biopolymer‐coated ultrasmall catalytic nanodots as a non‐pharmaceutical neuroprotective strategy for ischemic stroke treatment.