Local release of fibroblast growth factor 21 and cannabidiol promoting spinal cord nerve injury repair through activation of cannabinoid receptor 2.

Spinal cord injury (SCI) is a debilitating condition that leads to severe motor and sensory dysfunction, largely due to inflammation, neuronal damage, and disrupted neural circuits. In this study, we developed an injectable hydrogel (C/F/Gel) co-loaded with fibroblast growth factor 21 (FGF21) and cannabidiol micelles (CBDm) to enhance SCI repair. The hydrogel, composed of PF127 and α-cyclodextrin (α-CD), provides sustained drug release and improves drug stability at the injury site. Our findings demonstrate that C/F/Gel effectively modulates the inflammatory microenvironment by promoting microglial polarization toward the anti-inflammatory M2 phenotype via cannabinoid receptor 2 (CB2R) activation. Additionally, it regulates the balance between excitatory and inhibitory neurons, and significantly improves motor function in SCI mice. Behavioral assessments, histological analysis, and molecular studies confirmed the superior therapeutic efficacy of C/F/Gel compared to single-agent treatments. These results highlight C/F/Gel as a promising biomaterial-based strategy for SCI repair, offering a synergistic approach that integrates inflammation modulation, neuroprotection, and functional recovery.