Hyaluronic Acid Hydrogel‐Mediated Delivery of MSC‐Derived Exo‐FGF21 Promotes Spinal Cord Injury Repair via STAT3/SOCS3 Signaling

Spinal cord injury (SCI) initiates a cascade of secondary pathological events largely driven by neuroinflammation, where microglial polarization plays a pivotal role. Modulating microglial polarization from M1 to M2 phenotype has emerged as a promising therapeutic strategy. Fibroblast growth factor 21 (FGF21) is known to regulate inflammatory responses, but its delivery to the injury site remains challenging. In this study, we engineered a biocompatible hyaluronic acid (HA) hydrogel capable of sustained release of mesenchymal stem cell‐derived exosomes enriched with FGF21 (MSCs‐Exo‐FGF21). The hydrogel's physicochemical properties and release kinetics were characterized, and its cytocompatibility was verified in vitro. LPS‐stimulated microglial cells were used to evaluate polarization, cytokine profiles, and activation of the STAT3/SOCS3 signaling pathway. A rat SCI model was used to assess neuroprotection and functional recovery. MSCs‐Exo‐FGF21 promoted M2 polarization of microglia, suppressed M1 markers, and significantly activated the STAT3/SOCS3 pathway both in vitro and in vivo. ELISA and qPCR analyses revealed reduced proinflammatory cytokines (IL‐1β, TNF‐α) levels and elevated anti‐inflammatory IL‐10. In SCI rats, hydrogel‐mediated delivery of MSCs‐Exo‐FGF21 reduced lesion cavity size, preserved neuronal structure, and significantly improved hindlimb locomotor function. The hydrogel provided a favorable microenvironment for sustained exosome release and cellular uptake. Our findings demonstrate that hydrogel‐based delivery of MSCs‐Exo‐FGF21 effectively reprograms microglial polarization through STAT3/SOCS3 signaling, alleviates neuroinflammation, and promotes functional recovery after SCI. This exosome–hydrogel platform offers a promising therapeutic avenue for modulating immune responses and enhancing neural repair in central nervous system (CNS) trauma.