ROS/Glucose-Dissociable EGCG-Coated Oxygen-Supplying Nanocomposite Hydrogel for Diabetic Wound Therapy

Background: In diabetic wounds, a detrimental and persistent inflammatory environment characterized by impaired angiogenesis and concomitant hypoxia severely impedes wound healing. This study utilized phenylboronic acid-grafted quaternized chitosan (QCS-PBA) to encapsulate calcium peroxide (CaO 2 ) within the QCS-PBA matrix. Epigallocatechin gallate (EGCG) was then anchored onto the surface via phenylborate ester bonds to fabricate oxygen-producing nanoparticles (QP@Ca-E). Finally, the nanoparticles were integrated into a multifunctional hydrogel (GP-GL) prepared from functionalized gelatin. This system provides a promising therapeutic strategy for irregular wound closure, hypoxia alleviation, inflammatory response modulation, and angiogenesis promotion. Methods: In this study, QP@Ca-E loaded with CaO 2 and EGCG were combined with functionalized gelatin grafted with double bonds/lipoic acid (GP-GL) to fabricate a photocurable and reactive oxygen species (ROS)-responsive hydrogel delivery system (GP-GL@Ca-E). The system was systematically evaluated for its ROS/glucose-responsive release behavior, antioxidant activity, and antibacterial properties. Through in vitro experiments, the hydrogel’s biocompatibility and its effects on cellular ROS/hypoxia levels, angiogenic capacity, and macrophage polarization toward the M2 phenotype were further investigated. Additionally, a full-thickness skin defect model in diabetic rats was established to validate the hydrogel’s efficacy in promoting wound healing, restoring oxygen supply, mitigating inflammatory responses, and accelerating angiogenesis. Results: The GP-GL@Ca-E oxygen-supplying multifunctional hydrogel provides an effective physical barrier for irregular wounds. Moreover, the GP-GL@Ca-E hydrogel responds to ROS and glucose in the wound microenvironment to enable sustained EGCG release. EGCG not only exhibits excellent antibacterial, anti-inflammatory, and antioxidant properties but also promotes angiogenesis. Subsequently, the exposed CaO 2 reacts with water to continuously generate oxygen. The synergistic effect of EGCG and CaO 2 effectively alleviates wound hypoxia and inflammatory responses while promoting neovascularization, thereby creating a favorable microenvironment for diabetic wound repair and significantly accelerating the healing process. In vivo studies confirmed that compared with the control group, the hydrogel-treated group showed significantly accelerated wound healing. By day 14, the wound healing rate reached 99.01% in the hydrogel group, significantly higher than the 86.32% observed in the control group, fully demonstrating its great potential for diabetic wound therapy. Conclusion: The results indicate the successful preparation of a multifunctional oxygen-producing hydrogel, which exhibits remarkable antibacterial properties and ROS scavenging capability. This hydrogel can effectively suppress inflammatory responses, promote macrophage polarization toward the M2 phenotype, and enhance angiogenesis, thereby creating a favorable immune microenvironment for skin regeneration. These characteristics collectively demonstrate its promising potential for application in diabetic wound healing. Keywords: oxygen production, ROS/glucose-dissociable, EGCG-coated, diabetic wound therapy