Multifunctional Nanozyme Hydrogel for Oxidative Stress Scavenging and Mitophagy Activation in Spinal Cord Injury Repair.

Severe oxidative stress, persistent inflammation, and mitochondrial dysfunction during the secondary injury phase of spinal cord injury (SCI) severely impede regeneration. Here, we report a supramolecular hydrogel, Que@MCEu/H, engineered by metal-phenolic coordination between Quercetin (Que) and mesoporous Ce-doped europium oxide nanozymes (MCEu). This injectable system integrates the CAT/SOD-mimicking activities of MCEu with the therapeutic benefits of Que to achieve a multitargeted SCI intervention. In vitro, Que@MCEu/H efficiently scavenges reactive oxygen species, preserves mitochondrial ultrastructure, inhibits apoptosis, and drives macrophage polarization from M1 to M2, thereby remodeling the inflammatory microenvironment and alleviating oxidative-stress-induced neurite retraction. In vivo, Que@MCEu/H markedly reduces lesion cavities and fibrotic scarring in a mouse contusion SCI model, suppresses GFAP-positive glial scar formation, and promotes axonal regeneration and angiogenesis, culminating in improved locomotor function. Mechanistically, therapeutic outcomes correlate with upregulation of autophagy/mitophagy markers (Beclin-1, Parkin, LC3B), indicating enhanced clearance of damaged mitochondria and neuronal protection. Collectively, Que@MCEu/H offers a promising, multifunctional platform that couples antioxidation, immunomodulation, and mitochondrial protection to facilitate SCI repair and functional recovery.