Targeting Interleukin-6 Signaling with Reactive-Oxygen-Species-Responsive Hydrogel to Promote Regeneration after Spinal Cord Injury.

Spinal cord injury (SCI) triggers an excessive inflammatory response, characterized by the up-regulation of various inflammatory factors that impede neural regeneration and functional recovery. Interleukin-6 (IL-6) is an early and critical inflammatory mediator observed in lesions post-SCI. Antagonizing the signaling pathway presents a promising strategy to mitigate early inflammation and secondary injury after trauma. Here, we identified specific activation of the IL-6 receptor in neurons and microglia in lesions, indicating their responsiveness to early up-regulated IL-6 signaling within the microenvironment. In vitro, neutralizing IL-6 signaling in microglia effectively alleviated their inhibitory effects on neuronal axon growth in conditioned media. Building on this, we developed a reactive-oxygen-species-responsive hydrogel for the sustained local delivery of tocilizumab, an IL-6 receptor antagonist, and implanted it in a complete transection SCI model. In vivo, sustained IL-6 receptor blockade effectively reduced early inflammatory cell infiltration, modulated microglial polarization toward an anti-inflammatory phenotype, and fostered neuronal regeneration within the lesion. Importantly, this therapeutic intervention promoted long-term hind limb functional recovery in SCI mice. This study underscores the therapeutic potential of precisely targeting early inflammatory cytokine signaling pathways, particularly IL-6, to improve outcomes after SCI.