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

• A multifunctional coordination polymer nanozyme (Fe-FN CPs) was constructed using natural active compounds. • Fe-FN CPs alleviated oxidative stress by scavenging ROS and enhancing antioxidant defenses. • Fe-FN CPs modulated microglial polarization, reduced neuroinflammation, and protected mitochondrial and BBB integrity. • Fe-FN CPs improved cognitive outcomes after TBI, offering a promising nanomedicine strategy for neuroprotection. 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.