Iron Oxide Nanozyme as Reactive Oxygen and Nitrogen Species Scavenger to Regulate Microglial Homeostasis in Stroke

ABSTRACT In ischemic stroke, microglia adopt a pro–inflammatory M1‐like phenotype, which plays a pivotal role in the excessive production of nitric oxide radical (NO). The elevated levels of NO contribute to caspase‐mediated apoptosis, resulting in significant disruption of cerebral tissue architecture and consequent loss of brain function. In this study, we demonstrate that iron oxide nanoparticles (IONPs) with intrinsic enzyme–like activities can effectively scavenge NO by forming a nitrosyl‐metal complex. Specifically, 6 nm iron oxide nanoparticle (IONP6) exhibits enzyme‐like activities, superoxide dismutase (SOD) and catalase (CAT), thus potentially possessing the ability to scavenge the Reactive Oxygen and Nitrogen Species (RONS), especially the ability to scavenge NO. Furthermore, we show that IONP6 promotes the polarization of microglia toward the M2 phenotype, thereby alleviating neuroinflammation in both in vitro oxygen and glucose deprivation (OGD) and in vivo permanent middle cerebral artery occlusion (pMCAO) stroke models. This is achieved through the modulation of the HIF‐1α/TIM‐3 signaling axis in stroke rats. Additionally, IONP6 administration significantly reduces infarct size and improves neurological outcomes in stroke rats. Our findings position IONP6 as a promising drug‐free therapeutic agent for stroke, capable of regulating microglial polarization and mitigating secondary injury caused by the inflammatory cascade induced by NO.