ROS-Responsive Hydrogel with M2 Macrophage Nanovesicles for Diabetic Wound Healing: Targeted CO Delivery to Regulate Mitochondrial Metabolism and Reprogram Wound Microbiota

Macrophage dysregulation and microbial dysbiosis at diabetic chronic wound sites are two of the main drivers that hinder the healing process. To address this, a reactive oxygen species (ROS)-responsive hydrogel wound dressing (NVs@CO-TP) is fabricated through boronic ester bonds between poly(vinyl alcohol) hydroxyl groups and phenylboronic acid moieties, which incorporates M2 macrophage-derived nanovesicles (NVs) loaded with manganese carbonyl (NVs@CO). Upon exposure to a high level of ROS in the wound, the hydrogel responds, scavenges ROS, and subsequently releases NVs@CO, exhibiting the synergistic efficacy of CO gas and NVs. Due to its intrinsic inflammation-tendency ability, NVs@CO specifically targets activated M1 macrophages and releases CO to regulate mitochondrial metabolism, promoting M1 apoptosis and increasing the M2 phenotype. This process decreases the release of inflammatory cytokines and enhances anti-inflammatory processes, promoting chronic diabetic wound healing. More interestingly, the dressing also beneficially modulates the wound microbiota by enhancing the beneficial microbial richness and overall microbiome composition, which further improves the healing microenvironment. Therefore, NVs@CO-TP acts through two primary mechanisms: the targeted delivery of CO to M1 macrophages regulates the mitochondrial metabolism to repolarize macrophages while simultaneously modulating the wound microbiome. This combined anti-inflammatory strategy facilitates chronic wound healing and demonstrates significant potential for clinical translation in treating various difficult-to-heal wounds.