Bioinspired hydrogel remodels the niche after spinal cord injury for neural reconnection by promoting angiogenesis and reducing inflammation

Spinal cord injury (SCI) disrupts the local microenvironmental niche, resulting in persistent neuroinflammation, vascular dysfunction, and impaired neuronal regeneration, presenting a significant challenge for tissue repair. In this context, hydrogels offer a versatile strategy for targeted and sustained therapeutic delivery and localized microenvironmental modulation. To facilitate niche restoration following SCI, we developed a bioinspired platform by integrating KTPSLEQRTVYAKGGIKRGK-brain-derived neurotrophic factor mimetic peptides (TPS-BDNF) into a dopamine-modified gelatin methacryloyl hydrogel. In vitro and in vivo studies demonstrated that the proposed hydrogel exhibits optimal injectability, shear-thinning behavior, and intrinsic antioxidant and anti-inflammatory properties, thereby facilitating minimally invasive delivery and localized microenvironment modulation. Furthermore, the TPS-BDNF endows the multifunctional hydrogel with sustained neurotrophic and pro-angiogenic cues that promote the restoration of the neurovascular niche and subsequent functional recovery after SCI. In summary, the bioinspired hydrogel offers a promising, clinically translatable approach to synergistic niche remodeling for the restoration of neuronal function following SCI. STATEMENT OF SIGNIFICANCE: The gelatin methacryloyl (GelMA) /dopamine/Polyethylene glycol-conjugated KTPSLEQRTVYAKGGIKRGK-brain-derived neurotrophic factor mimetic peptides (TPS-BDNF) (GDP) hydrogel represents a significant advance for spinal cord injury (SCI) therapy by simultaneously promoting neurogenesis and angiogenesis while delivering strong anti-inflammatory and antioxidant effects. By integrating TPS-BDNF with a GelMA-based matrix, GDP remodels the lesion microenvironment, enhances endogenous neural stem cell mobilization and neuronal differentiation, and improves functional recovery in SCI animals, all with injectable, controllable release and minimal systemic toxicity. This platform holds strong potential for translation to human SCI treatment.