An NIR-responsive FeS-loaded alginate hydrogel promotes diabetic wound healing through Nrf2 activation and macrophage polarization

Abstract

Diabetic wounds are characterized by excessive oxidative stress, persistent inflammation, and impaired tissue regeneration, which collectively hinder normal wound healing. Here, we developed a near-infrared (NIR)-responsive sodium alginate hydrogel incorporating nano‑iron sulfide (nFeS) through mild gelation mediated by calcium carbonate and glucono-δ-lactone. The resulting SA-nFeS hydrogel exhibited a porous structure, favorable rheological properties, hydrogen peroxide-responsive degradation, radical-scavenging activity, and good cytocompatibility. NIR irradiation accelerated the release of Fe from the hydrogel, increasing the cumulative release from approximately 35.5% to 75.4% over 48 h. In cells exposed to oxidative stress, the NIR-treated SA-nFeS hydrogel markedly reduced intracellular reactive oxygen species and promoted Nrf2 nuclear translocation, accompanied by decreased Keap1 expression and increased expression of the downstream antioxidant proteins HO-1, SOD1, SOD2, and GPX4. Furthermore, the hydrogel suppressed pro-inflammatory macrophage markers and cytokines while increasing the expression of CD206, Arg-1, and IL-10, indicating a shift toward a pro-healing macrophage phenotype. In a streptozotocin-induced diabetic full-thickness wound model, SA-nFeS combined with NIR irradiation achieved approximately 93% wound-area reduction by Day 14 and promoted re-epithelialization, granulation tissue formation, and collagen deposition. No obvious histopathological abnormalities were observed in the major organs. Collectively, these findings demonstrate that the NIR-responsive SA-nFeS hydrogel promotes diabetic wound repair by activating endogenous antioxidant defense and modulating the inflammatory microenvironment, providing a promising therapeutic platform for chronic wound management.