BackgroundTraumatic spinal cord injury (SCI) causes neuronal death, demyelination, axonal degeneration, inflammation, glial scar formation, and cystic cavitation resulting in interruption of neural signaling and loss of nerve function. Multifactorial targeted therapy is a promising strategy for SCI.MethodsThe anti-inflammatory peptide KAFAKLAARLYRKALARQLGVAA (KAFAK) and brain-derived neurotrophic factor (BDNF)-modified hyaluronan-methylcellulose (HAMC) hydrogel was designed for minimally invasive, localized, and sustained intrathecal protein delivery. The physical and biological characteristics of HAMC-KAFAK/BDNF hydrogel were measured in vitro. SCI model was performed in rats and HAMC-KAFAK/BDNF hydrogel was injected into the injured site of spinal cord. The neuronal regeneration effect was evaluated by inflammatory cytokine levels, behavioral test and histological analysis at 8 weeks post operation.ResultsHAMC-KAFAK/BDNF hydrogel showed minimally swelling property and sustained release of the KAFAK and BDNF. HAMC-KAFAK/BDNF hydrogel significantly improved the proliferation of PC12 cells in vitro without cytotoxicity. Significant recovery in both neurological function and nerve tissue morphology in SCI rats were observed in HAMC-KAFAK/BDNF group. HAMC-KAFAK/BDNF group showed significant reduction in proinflammatory cytokines expression and cystic cavitation, decreased glial scar formation, and improved neuronal survival in the rat SCI model compared to HAMC group and SCI group.ConclusionThe HAMC-KAFAK/BDNF hydrogel promotes functional recovery of rats with spinal cord injury by regulating inflammatory cytokine levels and improving axonal regeneration.