A targeted triple-action redox-modulating hydrogel potentiates fibroblast-mediated repair to accelerate oral wound healing

Abstract

Oral mucosal defects cause persistent pain and impair essential orofacial functions, making rapid healing a clinical priority. However, the specific microenvironmental factors that limit mucosal repair are not fully characterized. Using single-cell transcriptomic profiling, we identified oxidative stress-mediated inhibition of fibroblast extracellular matrix (ECM) synthesis as a critical barrier to wound healing. To address this, we developed an injectable hydrogel (FA/Zn-KR/Gel) that incorporates ferulic acid (FA) and a Zn2+-coordinated Cys-KR-12 complex (Zn-KR) to orchestrate a triple-action redox modulation. The hydrogel attenuates upstream reactive oxygen species (ROS) production via bacterial clearance and macrophage pro-oxidative enzyme suppression, directly scavenges free radicals, and fortifies downstream fibroblast antioxidant capacity through NRF2/HO-1/NQO1 upregulation. This integrated redox modulation prevents oxidative stress-induced apoptosis and senescence while rescuing fibroblast proliferation, migration, and ECM synthesis. In a rat oral mucosal defect model, the hydrogel significantly accelerated wound closure and improved tissue maturation. These findings establish a translational pipeline from single-cell mechanistic discovery to targeted, redox-modulating strategies for oral wound healing.