Engineered mesenchymal stem cells-laden chondroitin sulfate hydrogel promotes diabetic wound healing through ROS scavenging and macrophage polarization

The treatment of diabetic wound complications has long been a formidable challenge in the clinic, and a multifunctional biomaterial dressing holds great promise as an ideal approach for promoting diabetic wound healing. In this study, we designed a crosslinked chondroitin sulfate (CS) and polyethylene glycol (PEG) hydrogel (CS gel) as a reservoir via a Michael addition reaction. To further enhance the biological functions, surface-engineered mesenchymal stem cells (MSCs) modified with bilirubin-modified chondroitin sulfate-mediated mixed micellar backpacks possessing ROS scavenging/responsive and CD44-targeting abilities (DCMMs) were incorporated into the hydrogel system. The hydrogel served as a physical carrier, providing a sustained-release platform that ensured the long-term presence and controlled delivery of MSCs-tethered micellar backpacks at the wound site. <i>In vitro</i> experiments revealed the remarkable capacity of the hydrogel for ROS scavenging and regulating macrophage polarization. <i>In vivo</i> investigations in diabetic mouse models further confirmed the therapeutic potential, revealing a significant acceleration of wound closure, attenuation of inflammation, and augmentation of angiogenesis. Overall, this innovative hydrogel system that encapsulates surface-engineered mesenchymal stem cells (MSCs-DCMMs) represents a promising remedy and a framework for stem-cell-based therapeutic systems to treat diabetic wounds.