Microenvironment‐Programmed siRNA‐Based Hydrogel for Spatiotemporal Gene Silencing in Wound Healing

Excessive inflammation and overexpressed matrix metalloproteinases (MMPs) are significant factors in the prolonged healing of chronic diabetic wounds. Here, a precise gene therapy strategy is proposed utilizing siRNA and employing intelligent responsive materials for controlled release to mechanistically intervene in the pathological process of chronic non-healing wounds. The system employs a cationic hyperbranched aminoglycoside with disulfide bonds (SS-HPT) as its core delivery mechanism. These SS-HPT/siRMMP-9 complexes are incorporated into a hyaluronic acid-based hydrogel with redox-responsive properties (OR-S gel), allowing dual regulation of reactive oxygen species (ROS) in the wound microenvironment. The hydrogel network actively scavenges excess ROS, mitigating oxidative stress damage to tissue repair. Simultaneously, ROS-mediated hydrogel degradation enables the controlled release of siRMMP-9, enhancing the treatment's spatiotemporal precision and biocompatibility. In vitro and in vivo experiments confirm that this treatment system effectively down-regulates MMP-9 expression, remodels the extracellular matrix, and enhances the wound repair microenvironment, thereby significantly accelerating the healing of chronic diabetic wounds. This study introduces an innovative intervention targeting the mechanisms underlying non-healing diabetic wounds and offers a theoretical foundation for applying intelligent responsive gene delivery systems in tissue repair, demonstrating promising translational potential and clinical prospects.