Microenvironment-responsive immunoregulatory hydrogel exerts multi-regulation and synergistic reprogramming of macrophages to promote diabetic wound healing

Diabetic foot ulcers pose a significant clinical challenge due to dysregulated immune responses, neuropathic complications, and persistent infections that synergistically disrupt physiological tissue regeneration mechanisms. While immune activation is essential for orchestrating wound repair, excessive inflammation often exacerbates tissue damage in chronic diabetic wounds. To address these multifactorial issues, we designed a dual-crosslinked hydrogel platform integrating alginate, Bletilla striata polysaccharides (BSP), and gelatin to encapsulate tannic acid/Fe 3+ (TA/Fe 3+ ) composite nanoparticles with synergistic photothermal antibacterial treatment function. In vitro studies demonstrated that the dual-crosslinked hydrogel modulated immune microenvironment through effective scavenging of pathological reactive oxygen species (ROS) and significant downregulation of pro-inflammatory cytokine expression and promoting fibroblast migration. In addition, TA/Fe 3+ endowed the hydrogel with antibacterial activity under near-infrared (NIR) irradiation. The macrophage phenotype study revealed that the hydrogel promoted anti-inflammatory phenotype reprogramming of bone marrow-derived macrophages (BMDMs) under lipopolysaccharide (LPS) stimulation, which may be achieved by down-regulating the nuclear expression of pyruvate kinase M2 (PKM2). In the in vivo evaluation of the diabetic mouse model, the ability of the hydrogel to accelerate wound closure was verified, and the neovascularization at the lesion site was strongly stimulated. Through the temporal and spatial control of the healing process, the hydrogel has become an integrated treatment platform for chronic infection wound management, showing potential clinical application value.