Multifunctional Diselenide-Based Antioxidative Nanozymes Promote Spinal Cord Repair via Oxidative Stress Alleviation and Immune Modulation.

Spinal cord injury could trigger an excessive reactive oxygen species formation and a sustained inflammatory response, both of which disrupt neural repair processes. Therefore, it is urgent that exploiting a therapeutic intervention that can simultaneously neutralize ROS and restore immune balance. This study reports a hyaluronic acid-based diselenide cross-linked nanogel (Se-Se@HA) designed to integrate catalytic ROS scavenging and immunomodulatory properties to reconstruct the damaged microenvironment and promote repair. Se-Se@HA exhibits significant structural stability and selectively responds to ROS, demonstrating strong free radical scavenging capabilities. By inhibiting M1 polarization and enhancing the M2 phenotype, Se-Se@HA reduces the levels of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, exhibiting potent anti-inflammatory effects. In vitro, Se-Se@HA protects neurons from oxidative stress damage and promotes neurite growth and axonal bridging. In vivo, this nanogel has demonstrated strong ROS scavenging and anti-inflammatory effects. Transcriptome analysis revealed downregulation of NF-κB, TNF, and MAPK signaling pathways, while enrichment of gene pathways related to synaptic transmission and regeneration. Functionally, Se-Se@HA significantly improved BMS scores, gait indices, and gait regularity, enhanced motor evoked potentials and electromyographic signals, reduced muscle atrophy; increased axonal continuity, restored serotonergic and synaptic-related signals at the injury site, and reduced scar formation. These findings suggest that Se-Se@HA is a multifunctional nanozyme platform capable of coordinating oxidative stress relief, immune homeostasis, and neuroregeneration, providing a promising therapeutic strategy for SCI.