Cascade-activated mussel-mimetic hydrogel with aurantiamide acetate nanoparticles reprograms macrophages and modulates ROS for accelerated diabetic wound healing

Diabetic chronic wounds (DCWs) are characterized by persistent oxidative stress, unresolved inflammation, and impaired angiogenesis. Here, we developed a cascade-activated, mussel-mimetic adhesive hydrogel (APAP) integrating dopamine-grafted hyaluronic acid for robust tissue adhesion, ROS-cleavable phenylboronic acid-modified poly(acrylic acid) for on-demand drug release, thermosensitive poloxamer 407 for in situ gelation, and aurantiamide acetate-loaded nanoparticles (ANPs). In vitro, APAP exhibited potent broad-spectrum antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) , efficient ROS scavenging, excellent cytocompatibility, and effectively reprogrammed macrophages from a pro-inflammatory M1 to a reparative M2 phenotype via PI3K/Akt activation and NF-κB suppression, generating a pro-angiogenic secretome. In streptozotocin-induced diabetic mice, a single application of APAP achieved 96.5% wound closure by day 14, accompanied by accelerated re-epithelialization, collagen deposition, and dermal appendage regeneration. Transcriptomic and protein analyses confirmed restoration of ECM-receptor interactions and activation of pro-survival PI3K/Akt signaling. This spatiotemporally coordinated platform offers a promising single-dose strategy for the effective management of diabetic chronic wounds.