Engineered Exosome‐Loaded Silk Fibroin Composite Hydrogels Promote Tissue Repair in Spinal Cord Injury Via Immune Checkpoint Blockade

Abstract Spinal cord injury (SCI) is a severe central nervous system disorder characterized by a high rate of disability and limited axonal regeneration. Excessive post‐injury inflammation often leads to further neuronal damage. Immune checkpoint (IC) genes, which regulate immune cell activity, play a critical role in modulating post‐injury 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‐containing protein 3 (Tim3) is highly expressed in microglia following SCI, contributing to an exacerbated inflammatory response. To address this, an RNAi‐Tim3‐Exo@SF hydrogel system is designed to deliver siRNA‐Tim3 via exosomes, thereby regulating Tim3 expression after injury. Furthermore, miRNA sequencing indicates that the engineered exosomes (RNAi‐Tim3‐Exo) encapsulated within the hydrogel have the potential to promote axonal regeneration and modulate the spinal cord microenvironment. Preclinical studies demonstrate that the RNAi‐Tim3‐Exo@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‐155‐5p contained within the RNAi‐Tim3‐Exo. By integrating bioinformatics, biomedical science, and tissue engineering, this study presents a novel hydrogel‐based therapeutic strategy with significant potential for the treatment of SCI.