Novel copper-ion coordinated andrographolide-loaded hydrogel activates Rac1/JNK1 axis for enhancing diabetic wound healing

Chronic diabetic wounds represent a major clinical challenge, compounded by persistent inflammation, microbial invasion, and deficient angiogenesis. To address these intertwined pathophysiological features, we developed a copper-ion coordinated andrographolide-loaded hydrogel (ASFH), significantly enhancing andrographolide solubility and promoting wound healing dynamics. In vitro assessments demonstrated superior antimicrobial activity, optimal mechanical strength, self-healing ability, and cytocompatibility. In diabetic mice, ASFH notably accelerated wound closure, stimulated collagen maturation and re-epithelialization, dynamically shifted macrophages toward an anti-inflammatory phenotype, and markedly enhanced angiogenesis. Mechanistic studies integrating network pharmacology, molecular docking, dynamics simulations, and SPR validation pinpointed the Rac1/JNK1/Jun/Fos signaling cascade as a primary mediator of these regenerative effects. This work presents ASFH as a translationally relevant dressing system, simultaneously addressing critical limitations in diabetic wound management through targeted molecular therapeutic intervention.