Adaptive ROS-Responsive Dual-Layered Hydrogel with Ginkgo Biloba-Derived Exosome-Like Nanovesicles for Diabetic Wound Healing.

Abstract

Impaired healing of diabetic wounds is frequently associated with persistent local infection and a dynamic imbalance in reactive oxygen species (ROS), which synergistically exacerbate tissue damage and complicate clinical management. Conventional single-layer hydrogel dressings often fail to meet the contradictory requirements of distinct wound-healing stages. This study developed a multifunctional bilayer hydrogel system (Dual-Gel) designed to promote wound healing by precisely regulating dynamic ROS levels in the wound microenvironment. The hydrogel was synthesized from a glycidyl methacrylate-modified ε-polylysine (EPLGMA) network loaded with copper ions (Gel 1) and a gelatin network crosslinked with an ROS-cleavable linker (NHS-TK-NHS) (Gel 2). During the infection phase, Gel 1 exerts antibacterial activity through ε-polylysine, which dissociates from the hydrogel matrix in the infected microenvironment, whereas the slowly released copper ions catalyze a Fenton reaction that converts H₂O₂ into bactericidal ROS. Subsequently, excessive ROS cleaves the NHS-TK-NHS linker in Gel 2, leading to the degradation of the hydrogel and the release of exosomes. These exosomes promote cell proliferation and angiogenesis while upregulating anti-apoptotic factors. Ultimately, the Dual-Gel system orchestrates the precise release of bioactive components by responding to dynamic changes in wound ROS, offering a novel regulatory strategy for managing complex diabetic wounds.