Programming the Diabetic‐Infected Wound Microenvironment With a Smart Hydrogel for Ordered Healing Cascade Restoration

ABSTRACT

The diabetic‐infected wound microenvironment, marked by elevated reactive oxygen species (ROS) levels, ongoing inflammation, and defective angiogenesis, interferes with the normal wound healing cascade and contributes to delayed and treatment‐resistant repair. However, most existing wound dressings lack the capability to dynamically adapt to these spatiotemporally evolving conditions. Herein, a smart and microenvironment‐programmable PVH‐ST hydrogel is developed to achieve phased and spatiotemporally coordinated regulation of diabetic‐infected wound healing. The hydrogel is engineered by integrating strontium (Sr)‐tannic acid (ST) nanoparticles into a polyvinyl alcohol (PVA) and hyaluronic acid (HA) matrix through a boric acid‐mediated multilevel dynamic crosslinking network, endowing the system with mechanical robustness suitable for daily motion. Upon wound occurrence, the PVH‐ST hydrogel rapidly induces hemostasis and establishes a bioactive provisional matrix. In response to the ROS‐enriched infected microenvironment, the dynamic borate bonds undergo on‐demand dissociation, triggering controlled release of ST nanoparticles. Released ST nanoparticles integrate antibacterial and antioxidant functions and reduce inflammatory burden via modulation of NF‐κB signaling and skewing macrophages toward an M2 pro‐regenerative state. Concurrently, the sustained release of Sr ²⁺ ions activates VEGF‐associated angiogenic signaling and epithelialization pathways, thereby promoting vascularization and epithelial reconstruction for diabetic‐infected wounds.