Sequentially triggered triple-responsive hydrogels for targeted regulation of inflammation and angiogenesis in diabetic-infected wound healing

Bacterial infection, excessive inflammatory response, and impaired angiogenesis caused by the hyperglycemic microenvironment of diabetic wounds are the primary factors of non-healing wounds. Most contemporary wound repair materials passively release loaded drugs, resulting in poor therapeutic outcomes. In this study, we designed sequentially triggered triple-responsive hydrogels containing alginate (ALG)-phenylboronic acid (PBA), copper polydopamine (Cu-PDA), metformin (MET), and deferoxamine mesylate (DFO) to cover the continuous process of diabetic-infected wound healing and improve the wound microenvironment through warming in the infectious phase and on-demand drug release in the inflammatory and proliferative phase. The hydrogels exhibited good adhesivity, injectability, self-healing ability, and biocompatibility. The hydrogels show remarkable photothermal responsiveness due to the presence of PDA. Studies showed that appropriate high temperatures and the release of Cu²⁺ resulted in the hydrogels displaying excellent bactericidal properties in the infectious phase. Furthermore, the instability of the phenyl borate bond in a hyperglycemic and acidic microenvironment enables the glucose/pH responsiveness of the release of MET and DFO from the hydrogels. Mechanistic studies have shown that the hydrogels could suppress the activity of the NOD-, LRR-, and pyrin structural domain-containing protein 3 (NLRP3)/caspase-1/GasderminD (GSDMD)/IL-1β pathway and activate the hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF) pathway. These effects enabled the hydrogels to promote the healing of diabetic-infected wounds.