Fe-Formononetin nanoenzymes promote traumatic brain injury repair by alleviating oxidative stress and regulating microglia polarization

Traumatic brain injury (TBI) is characterized by oxidative stress, neuroinflammation, and microglial dysregulation, leading to secondary neuronal damage. Here, we constructed coordination polymer nanoenzymes (Fe-FN CPs) with multiple enzyme-like activities and favorable biocompatibility. In vitro, Fe-FN CPs suppressed ROS accumulation, reduced pro-inflammatory cytokine release, and promoted microglial polarization toward the M2 phenotype. In vivo, Fe-FN CPs enhanced antioxidant defense, alleviated mitochondrial damage and cerebral edema, restored blood–brain barrier integrity, and improved cognitive performance. Mechanistically, Fe-FN CPs achieved dual regulation by inhibiting pro-inflammatory M1 polarization while promoting anti-inflammatory M2 polarization. These findings demonstrate that Fe-FN CPs exert potent neuroprotective effects and provide a promising nanomedicine strategy for TBI therapy based on natural active compounds.