Time-ordered crosslinked hydrogel for full-cycle therapy of chronic wounds

Bacterial infections and excessive inflammation complicate wound healing in diabetes. Current dressings predominantly target a single aspect of the healing process, underscoring the urgent need for chronic wound dressings that regulate the entire healing trajectory. Herein, we designed a dual-crosslinked hydrogel (Que@HZ) via a stepwise fabrication process to achieve the staged release of Zn²⁺ and quercetin. Quercetin-loaded gelatin nanoparticles (Que NPs) were incorporated into the primary chemical network synthesized via HA-Nor photopolymerization. Subsequently, a secondary physical crosslinking step using Zn²⁺ was employed to establish a dual crosslinked network. This sequential design imparts stage-specific functions to the hydrogel. The incorporation of Zn²⁺ not only enhanced the mechanical properties but also provided sustained antibacterial efficacy (antibacterial rate > 95% against S. aureus for over seven days), thereby preventing early-stage infection. Concurrently, the integration of Que. NPs via hydrogen bonds endowed the system with pH-responsive and sustained-release capabilities, facilitating antioxidant and anti-inflammatory effects during the mid-to-late stages of healing. In vivo experiments using diabetic SD rats with chronic wounds, combined with RNA-sequencing analysis, demonstrated that Que.@HZ eliminated infections via its bactericidal activity while reducing inflammation and promoting angiogenesis and collagen deposition by modulating the IL-17 pathway. In conclusion, this study presents Que.@HZ as an advanced design for smart dressings that integrate multifunctionality with full-cycle regulation, offering a promising strategy for the management of chronic wounds.