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

Abstract 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.