Multifunctional and immunoregulatory microenvironment-responsive hydrogel for whole course management of infected diabetic wounds

Creating a multifunctional microenvironment-responsive ATAN-Met hydrogel system promotes infective diabetic wound healing by enhancing re-epithelialization, neurovascular-hair follicles regeneration, antibacterial and immunoregulation. • A novel strategy using a microenvironment-responsive ATAN-Met hydrogel system to promote infective diabetic wounds healing. • The hydrogel has impressive self-healing and wearable properties, responding to high Glucose/ROS for drug release. • The system exhibited anti-bacterial, reduced inflammation, promoted nerve regeneration and hair follicle regrowth. • The system activated the Hippo pathway, inhibit the TNF pathway to improve the diabetic wound healing. Infective diabetic wounds can significantly delay healing and pose severe infection risks. The process of infective diabetic wounds healing (DWH) are not only re-epithelialization and angiogenesis but also anti-bacterial, hair follicles regeneration and nerve growth. In this study, a stable dynamic hydrogel system was formulated by incorporating dynamic borate easter bond and carbon–carbon double bond, which based on tannic acid (TA) − acrylic phenyl boric acid (APBA) and acrylamide (AM). Subsequently, a hydrogel (ATAN-Met) was obtained by modifying the antibacterial ammonium cationic (N + ) and loading metformin (Met). This system demonstrated impressive wet adhesion, self-healing, wearable and peelable properties, responding to glucose/reactive oxygen species (ROS) for drug release. In vitro and vivo experiments illustrated that ATAN-Met recruited mesenchymal stem cell (MSC), facilitating interaction between MSC and neural cells, regulating macrophage polarization, and modulating the diabetic wound microenvironment while exhibiting anti-bacterial property, ultimately leading to re-epithelialization and neurovascular-hair follicles regeneration. RNA and metabolomic sequencing indicated that ATAN-Met activate the Hippo pathway, inhibit the TNF pathway, and regulate wound metabolism to improve the diabetic wound microenvironment. These results suggest that the microenvironment-responsive ATAN-Met hydrogel shows considerable potential for the whole course management of infective DWH.