Dynamically responsive hydrogel with mechanical stimulation enhances diabetic wound healing via activation of Piezo1-mediated efferocytosis

Correcting the disordered metabolism and achieving dynamic, comprehensive management of chronic diabetic wounds remains a significant challenge. This study presents a double-network dynamic hydrogel exhibiting long-term anti-inflammatory, antioxidant properties, and tunable mechanical strength. The hydrogel is primarily composed of modified chitosan, hyaluronic acid, sodium alginate, and ZnO 2 /Fe 3+ nanoparticles. The incorporated ZnO 2 /Fe 3+ nanoparticles enable microenvironmental regulation by responding to H + or reactive oxygen species (ROS), while the released Fe 3+ ions drive hydrogel network reconstruction, thereby enhancing mechanical properties. In vitro studies demonstrate the hydrogel's efficacy in efficiently scavenging ROS and enhancing Piezo1-mediated macrophage efferocytosis through cell-matrix interactions, accelerating macrophage polarization towards the M2 phenotype and resolving inflammation. In vivo experiments further confirm that the CHS@ZnO 2 /Fe 3+ hydrogel significantly promotes re-epithelialization. Mechanical stimulation provided by the hydrogel recruited abundant fibroblasts and endothelial cells to the wound site, facilitating collagen deposition and angiogenesis. This novel hydrogel dressing, combining mechanical and biochemical dual-regulation, provides an advanced therapeutic strategy for the efficient repair of diabetic chronic wounds. • Here, we develop a novel CHS@ZnO 2 /Fe 3+ double-network hydrogel based on chitosan-hyaluronic acid-sodium alginate, integrating the biocompatibility, adhesiveness, and biodegradability inherent to natural polysaccharides. Key innovations include: • Metabolic Reprogramming & Microenvironment Remodeling: The hydrogel effectively scavenges reactive oxygen species (ROS) and facilitates lactate clearance. • Immunomodulation & Antibacterial Action: Zn 2+ ions promote macrophage M2 polarization and confer robust antibacterial properties. • Fe 3+ ions trigger a dynamic reorganization of the alginate network via coordination interactions, leading to a self-stiffening effect that provides sustained mechanical support for tissue regeneration. • Enhanced Efferocytosis: Piezo1-mediated augmentation of macrophage phagocytosis clears apoptotic cells, alleviates inflammation, and further drives polarization toward the pro-regenerative M2 phenotype. • Mechanotransduction via Piezo1/YAP Pathway: The enhanced matrix stiffness provides sustained mechanical signaling, activating the Piezo1/YAP pathway to stimulate fibroblast proliferation, adhesion, and migration. • Self-Contained Therapeutic System: The hydrogel accomplishes these functions without relying on any exogenous biological agents, highlighting its self-sufficient nature and translational potential.