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.