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Spinal cord injury may trigger excessive reactive oxygen species (ROS) production and persistent inflammatory responses, both of which disrupt the neural repair process. Therefore, there is an urgent need for a therapeutic intervention that can both neutralize ROS and restore immune balance. This study reports a hyaluronic acid-based diselenide-crosslinked nanogel (Se–Se@HA), designed to integrate catalytic ROS scavenging and immunomodulatory capabilities to reconstruct the damaged microenvironment and promote repair. Se–Se@HA demonstrates remarkable structural stability and selectively responds to ROS, showing strong free radical scavenging ability. By inhibiting M1 polarization and enhancing the M2 phenotype, Se–Se@HA reduces 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-induced damage and promotes neurite outgrowth and axonal bridging. In vivo, this nanogel shows robust ROS scavenging and anti-inflammatory effects. Transcriptomic analysis reveals downregulation of NF-κB, TNF, and MAPK signaling pathways, alongside enrichment of genes related to synaptic transmission and regeneration. Functionally, Se–Se@HA significantly improves Basso Mouse Scale scores, gait indices, and gait regularity, enhances motor evoked potentials and electromyography signals, reduces muscle atrophy; it increases axonal continuity, restores serotonergic and synapse-related signaling at the injury site, and decreases scar formation. These findings suggest that Se–Se@HA is a multifunctional nanozyme platform capable of coordinating oxidative stress alleviation, immune homeostasis, and neural regeneration, offering a promising therapeutic strategy for spinal cord injury.
