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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\u00a0vitro, 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\u00a0vivo, 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.<\/jats:p>","DOI":"10.34133\/bmr.0395","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T20:47:58Z","timestamp":1782938878000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Targeting Interleukin-6 Signaling with Reactive-Oxygen-Species-Responsive Hydrogel to Promote Regeneration after Spinal Cord Injury"],"prefix":"10.34133","volume":"30","author":[{"given":"Runlin","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, College of Life Sciences, \rCentral South University, Changsha 410078, China."},{"name":"Department of Neurosurgery, \rXiangya Hospital of Central South University, Changsha 410008, 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