Sustained-Release Spermidine Hydrogel Inhibits M1 Macrophage Polarization and Promotes Tissue Repair for Spinal Cord Injury Repair.

The use of injectable hydrogels represents a viable approach for enhancing neural repair and promoting functional restoration after spinal cord trauma. Nevertheless, the current performance of these materials is not yet optimal and further optimization is necessary. Engineering a cell-free hydrogel delivery system with sustained anti-inflammatory capacity is of great relevance for advancing therapeutic strategies in spinal cord injury (SCI). Here, we fabricated a biomimetic hydrogel incorporating spermidine to modulate the post-injury immune microenvironment. The material was constructed by photocrosslinking aldehyde-modified methacrylated hyaluronic acid (AHAMA) through dynamic Schiff base chemistry, enabling controlled and prolonged spermidine release. This hydrogel demonstrated expedited gelation kinetics coupled with stable and exceptional mechanical properties. In addition, the cell-free AHAMA hydrogels have substantially enhanced the cellular-matrix interactions and facilitated neuronal integration. Furthermore, the spermidine-loaded hydrogel exerted potent immunomodulatory effects by suppressing M1 macrophage (classically activated macrophage) polarization through activation of STAT1 (signal transducer and activator of transcription 1) signaling axis. In vivo assessments demonstrated enhanced neuroregeneration and axonal elongation at the lesion site, which translated into marked improvements in locomotor function in the murine SCI model. Collectively, the combination of sustained spermidine release with a bioinspired, cell-free AHAMA hydrogel scaffold offers an effective therapeutic approach to modulate inflammation and enhance tissue repair in the injured spinal cord environment.