Astaxanthin-metformin conjugate nanomicelles-loaded hydrogel reprograms macrophage metabolism via mitochondrion-targeted regulation for diabetic wound healing

Diabetic wounds struggle to heal because of ROS-mediated immune dysfunction, in which the mitochondrial metabolic reprogramming of macrophages is critical for inflammation resolution and tissue repair. Here, we innovatively combine the antioxidant astaxanthin (Ast) and the metabolic activator metformin (Met) via pH-responsive dynamic Schiff base linkages to form amphiphilic Ast-PEG-Met conjugates, which self-assemble into nanomicelles (NMs). This strategy effectively improves the solubility of Ast and enables synergistic delivery of the two complementary drugs. NMs target macrophage mitochondria, where Ast scavenges mtROS and Met activates energy metabolism pathways in a synergistic manner. The two drugs synergistically activate the AMPK-PPARγ axis and promote mitophagy, thereby restoring mitochondrial function and regulating immunometabolic reprogramming. For on-demand release, the NMs were further encapsulated into a ROS-responsive self-healing hydrogel crosslinked by dynamic phenylboronate ester bonds. This system responds to high levels of ROS and an acidic wound microenvironment with favorable biocompatibility. In a diabetic full-thickness skin defect model, this integrated platform markedly accelerated wound healing, promoted collagen deposition and angiogenesis, and alleviated chronic inflammation. This work provides a promising combined strategy involving antioxidant–metabolic regulation for chronic diabetic wound therapy via a dual-responsive hydrogel drug delivery system.