Glucose/ROS-responsive and redox-gated adaptive hydrogel dressing for accelerating diabetic wound repair via synergistic cGAS/STING pathway inhibition and oxidative stress alleviation

Persistent hyperglycemia-induced mitochondrial oxidative stress causes mtDNA leakage, activating the STING signaling pathway in macrophages and eliciting sustained pro-inflammatory cytokine secretion, resulting in wound healing stagnation throughout the inflammatory phase. In this study, we developed a glucose/ROS-responsive hydrogel dressing (SG) employing dynamic crosslinking via boronate ester between chlorogenic acid (CGA)-conjugated gelatin and sodium alginate functionalized with 3-aminophenylboronic acid. Furthermore, the engineered macrophage-targeting phosphatidylserine (PS)-incorporated liposomes (HPSL), designed for the precise delivery of the STING inhibitor H151, were incorporated into the hydrogel (HPSL@SG). This hydrogel exhibits superior injectability, stretchability, self-healing properties, and adaptation to the irregular shapes of skin wounds. Upon injection into a diabetic wound, the as-prepared hydrogel disintegrated in response to elevated glucose and ROS, facilitating the on-demand release of CGA and HPSL. The CGA can directly scavenge ROS to alleviate oxidative stress, achieving a 79.9% reduction in superoxide anion levels; the HPSL specifically targets macrophages to prevent disturbance of immunologic homeostasis due to off-target effects. This process facilitates macrophage polarization towards an anti-inflammatory phenotype by inhibiting the STING signaling pathway, thereby suppressing the release of pro-inflammatory cytokines TNF-α and IL-6 and promoting the release of IL-10. The HPSL@SG hydrogel collectively enhances angiogenesis, evidenced by a 6.6-fold increase in CD31 levels and a 7.3-fold increase in VEGF levels, while also facilitating collagen deposition, with collagen content escalating from 32.6% to 69.3%. This procedure culminates in an 89.7% recovery within 10 days and nearly complete wound healing within 14 days, indicating its potential for clinical application in diabetic wound healing.