Smart hydrogels modulate neutrophil fate to restore immune surveillance and homeostasis in diabetic wound healing

Diabetic wounds are highly susceptible to bacterial infection and exhibit impaired healing largely driven by defective neutrophil function. Herein, we developed an immunomodulatory hydrogel hybridized with a diselenide-bridged polymer (HHD) to regulate neutrophil fate for effective wound management. HHD demonstrates stepwise, glucose- and ROS-responsive drug release. The initially released l-arginine and pyridoxamine improve wound microenvironment by promoting angiogenesis and suppressing advanced glycation end products. Upon infection, this remodeled microenvironment enhances the recruitment and antibacterial capacity of neutrophils, enabling diabetic wounds to regain the ability to form early inflammatory zones and promptly clear invasive bacteria. Furthermore, excessive ROS generated from antimicrobial immunity degrades neutrophil-targeted polymers, releasing an NLRP3 inhibitor that suppresses inflammasome overactivation and accelerates neutrophil apoptosis, thereby facilitating macrophage efferocytosis to initiate tissue repair. We tracked HHD-shaped neutrophils and confirmed their efficacy in preventing infection and accelerating wound healing. Collectively, HHD represents a promising treatment platform for neutrophil-dependent diabetic wound care. STATEMENT OF SIGNIFICANCE: Neutrophil dysfunction is a key factor leading to infection and impaired healing of diabetic wounds. Significant challenges remain in achieving comprehensive regulation of neutrophil fate. In this work, we construct an immunomodulatory composite hydrogel to regulate neutrophil fate in diabetic wounds: 1) Improving the wound microenvironment, enhancing neutrophil recruitment, and strengthening its antibacterial activity; 2) Inducing neutrophil apoptosis through the neutrophil-targeting polymer; 3) Facilitating macrophage efferocytosis and phenotypic switching via apoptotic neutrophils, thereby expediting tissue repair.