Near-infrared-responsive silk/dopamine/fucoidan hydrogel incorporating multilayered silk-based nanoparticles as a reservoir for sequential and triggered NAC/NT delivery in diabetic wound healing.

Chronic diabetic wounds are characterized by excessive oxidative stress and impaired angiogenesis, presenting significant challenges for effective treatment. Herein, we developed a near-infrared (NIR)-responsive reservoir hydrogel (SD-NFA@SD/FC) capable of sustained and sequential drug delivery to promote diabetic wound healing. Free fucoidan (FC) was incorporated into a silk fibroin/dopamine (SD) hydrogel for early antioxidant and anti-inflammatory effects. Neurotensin (NT) and acetylcysteine (NAC) were sequentially assembled onto SD nanoparticles (224.61 ± 2.89 nm; zeta potential 1.36 ± 0.43 mV) via layer-by-layer (LbL) deposition and embedded within the hydrogel. The resulting system achieved sequential drug release, with rapid FC release within 24 h and sequentially sustained NAC and NT release for up to 10 days. Upon NIR triggering, NAC and NT showed enhanced release, increasing by approximately 10.6% and 15.0%, respectively, compared to the non-irradiated condition. In vitro, the hydrogel exhibited excellent biocompatibility and antioxidant activity while accelerating fibroblast migration to achieve complete wound closure within 12 h. In vivo, the NIR-triggered hydrogel markedly accelerated diabetic wound healing, achieving near-complete wound closure at day 14 with enhanced re-epithelialization, increased CD31+ vessel density, and reduced CD68+ macrophage infiltration. Accordingly, the NIR-responsive nanocomposite hydrogel represents a promising strategy for diabetic wound therapy.