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

## TL;DR

A smart hydrogel dressing accelerates diabetic wound healing by reducing inflammation and oxidative stress through targeted delivery of a STING pathway inhibitor.

## Contribution

A glucose/ROS-responsive hydrogel with macrophage-targeted STING inhibition is developed for diabetic wound healing.

## Key findings

- The hydrogel reduces superoxide anion levels by 79.9% and promotes macrophage M2 polarization.
- Angiogenesis increases with 6.6-fold CD31 and 7.3-fold VEGF level elevations.
- Wound healing reaches 89.7% recovery within 10 days and nearly complete healing in 14 days.

## Abstract

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.

Image 1

•The hydrogel reactivates stalled healing processes by remodeling redox homeostasis and the inflammatory microenvironment.•The released HPSL can precisely deliver H151 to macrophages, thereby driving macrophage M2 polarization via STING inhibition.•The hydrogel exhibits injectability, stretchability, self-healing, and adaptation to the irregular shapes of skin wounds.

The hydrogel reactivates stalled healing processes by remodeling redox homeostasis and the inflammatory microenvironment.

The released HPSL can precisely deliver H151 to macrophages, thereby driving macrophage M2 polarization via STING inhibition.

The hydrogel exhibits injectability, stretchability, self-healing, and adaptation to the irregular shapes of skin wounds.