Injectable silk fibroin hydrogel encapsulating pH-Responsive ZnS nanoparticles for synergistic redox modulation and diabetic wound healing.

Chronic diabetic wounds remain a major clinical challenge due to excessive reactive oxygen species (ROS), persistent inflammation, and impaired cellular function. Current wound dressings offer limited capacity to simultaneously regulate redox imbalance and support tissue regeneration, highlighting the necessity for adaptive, intelligent, and multifunctional platforms for regenerative therapy. Herein, we developed an injectable hydrogel system composed of methacrylated silk fibroin (SilMA) and aqueous-phase, pH-sensitive zinc sulfide nanoparticles (ZnS NPs). Spherical ZnS NPs were synthesized via a green aqueous-phase hydrothermal method, offering stable colloidal properties and controlled release of therapeutic H₂S and Zn under different pH conditions. Upon UV crosslinking, SilMA formed a porous, shear-thinning hydrogel (SF hydrogel) that facilitates in situ application and localized drug delivery. ZnS NPs were loaded into SF hydrogels and the resulting SF/ZnS hydrogel exhibited suitable mechanical strength, swelling and biodegradability for wound healing application. In vitro studies demonstrated the ZnS NPs' potent ROS-scavenging capacity and cytocompatibility, while the SF/ZnS hydrogel effectively restored fibroblasts and endothelial cells' function under oxidative stress and promoted macrophage polarization toward a reparative M2 phenotype. In a streptozotocin-induced diabetic mouse model, SF/ZnS hydrogel significantly accelerated wound closure, enhanced re-epithelialisation and collagen remodelling, and promoted neovascularization, while mitigating chronic inflammation. The SF/ZnS hydrogel developed in this study presents a promising therapeutic platform for chronic diabetic wounds, integrating redox regulation, immunomodulation, and regenerative enhancement within a single injectable system.