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 H 2 O 2 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.