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

Shiyu Sun,1,* Rongxue Zhu,1,* Junneng Du,1 Jin Lin,1 Yuying Li,1 Qian Jiang,1 Tianzong Huang,1 Enping Huang,2 Yingping Jiang,1 Xiaoya Zhang1 1Department of Rehabilitation Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, 510310, People’s Republic of China; 2Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingping Jiang; Xiaoya Zhang, Department of Rehabilitation Medicine, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, Guangdong, 510310, People’s Republic of China, Email [email protected]; [email protected]: 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 (CaO2) 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 CaO2 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 CaO2 reacts with water to continuously generate oxygen. The synergistic effect of EGCG and CaO2 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