Hydrogel delivering self-assembled herbal nanoparticles accelerates diabetic wound healing through mitochondrial regulation

The persistence of inflammation and mitochondrial dysfunction poses considerable challenges in the process of diabetic wound healing. Evidence from earlier research has revealed the significant activation of inflammation-related pathways in diabetic wound tissues. Thus, controlling inflammation may be the key to resolving non-healing diabetic wounds. Natural product-derived naringenin (Nar) and curcumin (Cur) can synergistically exert anti-inflammatory effects and accelerate mitochondrial repair. These compounds can promote the repair of damaged cells by improving mitochondrial function (restoring membrane potential, alleviating calcium overload, and inhibiting mitochondrial reactive oxygen species [ROS] production). Furthermore, they can activate the Nrf2/HO-1 pathway to enhance endogenous antioxidant defenses (SOD and CAT) and upregulate anti-inflammatory pathways, thus effectively suppressing NF-κB-mediated inflammatory cascades. In this study, we constructed a self-assembled herbal nanoparticle delivery system (NC NPs) composed of Nar and Cur. To enhance the applicability of this system for skin wounds, we prepared NC@Gel, a biocompatible thermo-sensitive hydrogel loaded with the NC NPs. In vivo experiments confirmed that NC@Gel not only provided synergistic anti-inflammatory and antioxidant effects but also regulated the phenotypic transition of macrophages, inhibits the secretion of pro-inflammatory factors, and ultimately promotes tissue regeneration in diabetic wounds. These findings shed light on the molecular mechanism through which NC@Gel exerts therapeutic effects via the Nrf2/NF-κB/mitochondrial functional axis. Overall, this study provides a novel nanomedicine-based strategy that could be translated for the clinical treatment of diabetic chronic wounds. The NC@Gel nanosystem is prepared via the self-assembly of the natural small molecules naringenin and curcumin into nanoparticles and the loading of these nanoparticles into a biocompatible hydrogel. This system effectively limits inflammation in diabetic wounds through three primary mechanisms: immune suppression, reactive oxygen species (ROS) scavenging, and mitochondrial repair. • NC@Gel synergistically exerted anti-inflammatory effects and accelerated mitochondrial repair. • NC@Gel activated the Nrf2/HO-1 pathway to enhance endogenous antioxidant defenses and upregulated anti-inflammatory pathways. • NC@Gel regulated the phenotypic transition of macrophages, and ultimately promoted tissue regeneration in diabetic wounds.