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Excessive post\u2010injury inflammation often leads to further neuronal damage. Immune checkpoint (IC) genes, which regulate immune cell activity, play a critical role in modulating post\u2010injury inflammation and thus influence neural repair and functional recovery. In this study, analysis of the GEO database reveals that the IC gene T cell immunoglobulin and mucin domain\u2010containing protein 3 (Tim3) is highly expressed in microglia following SCI, contributing to an exacerbated inflammatory response. To address this, an RNAi\u2010Tim3\u2010Exo@SF hydrogel system is designed to deliver siRNA\u2010Tim3 via exosomes, thereby regulating Tim3 expression after injury. Furthermore, miRNA sequencing indicates that the engineered exosomes (RNAi\u2010Tim3\u2010Exo) encapsulated within the hydrogel have the potential to promote axonal regeneration and modulate the spinal cord microenvironment. Preclinical studies demonstrate that the RNAi\u2010Tim3\u2010Exo@SF hydrogel could stabilize microtubules, promote damaged axon regeneration, stimulate angiogenesis, modulate the inflammatory environment, and ultimately improve motor function in SCI mouse models. Mechanistically, these reparative effects may be associated with miR\u2010155\u20105p contained within the RNAi\u2010Tim3\u2010Exo. By integrating bioinformatics, biomedical science, and tissue engineering, this study presents a novel hydrogel\u2010based therapeutic strategy with significant potential for the treatment of SCI.<\/jats:p>","DOI":"10.1002\/smll.202412170","type":"journal-article","created":{"date-parts":[[2025,5,19]],"date-time":"2025-05-19T03:54:46Z","timestamp":1747626886000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Engineered Exosome\u2010Loaded Silk Fibroin Composite Hydrogels Promote Tissue Repair in Spinal Cord Injury Via Immune Checkpoint Blockade"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0678-4056","authenticated-orcid":false,"given":"Xiaoyu","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital and Yuying Children's Hospital Wenzhou Medical University  Wenzhou Zhejiang 325000 China"},{"name":"Oujiang 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