Abstract
Diabetic wounds are characterized by chronic inflammation, vascular insufficiency, and peripheral neuropathy, which collectively disrupt the neurovascular microenvironment essential for coordinated tissue regeneration. However, strategies targeting neurovascular regeneration remain limited. Here, we developed a sprayable hydrogel sponge based on gelatin methacryloyl and methacrylamide-modified ε-poly-L-lysine (S-GPL), co-functionalized with VEGF-mimetic peptide (KLT) and BDNF-mimetic peptide (RGI). The sprayable format conforms to irregular wound geometries, while the pneumatic spraying technique generates high-pressure microbubbles that create a porous structure, thereby enhancing exudate absorption and sustained peptide release as a sponge dressing. Additionally, the incorporation of KLT and RGI facilitates the reconstruction of the neurovascular microenvironment. In vitro, KLT promoted endothelial cell maturation and cytokine secretion, whereas RGI enhanced Schwann cell activity. Notably, S-GPL(KLT/RGI) facilitated intercellular interactions between RSCs and HUVECs, highlighting the cellular mechanisms underlying neurovascular communication. In a full-thickness diabetic wound model in rats, the hydrogel accelerated wound closure, re-epithelialization, and matrix remodeling. These effects were accompanied by enhanced neovascularization and axonal regeneration, along with the formation of a spatially organized neurovascular niche, as evidenced by CD31(+) capillaries closely aligned with PGP9.5(+) nerve fibers. Building upon the intrinsic anti-inflammatory properties of S-GPL, transcriptomic and immunohistochemical analyses further revealed that S-GPL(KLT/RGI) treatment suppressed the IL-17 signaling pathway. However, the relationship between immunomodulation and neurovascular reconstruction warrants further investigation. Collectively, this study presents a sprayable antibacterial hydrogel that not only reconstructs the neurovascular microenvironment but also mitigates chronic inflammation, offering a clinically translatable strategy for diabetic wound management.