Bioresponsive Dual Microspheres Embedded in a Hydrogel: A Sequentially Triggered Strategy for Regulating Diabetic Wound Healing

ABSTRACT Chronic diabetic wounds complicated by methicillin‐resistant Staphylococcus aureus ( S. aureus ) (MRSA) remain refractory because the milieu evolves from a protease‐ and bacteria‐dominated inflammatory phase to a reactive oxygen species (ROS)‐rich, angiogenesis‐impaired reparative phase. Here we report a stage‐adaptive hydrogel dressing that integrates orthogonal, pathology‐stage–driven activation with pathological‐factor neutralization coupled to triggered delivery. Two bioresponsive microspheres are embedded in the hydrogel: MMP‐9–responsive gelatin methacrylate (GelMA) microspheres loaded with a cationic antimicrobial peptide (ILRWPWWPWRRK‐NH 2 ), and ROS‐responsive HA–PBA–PVA microspheres loaded with vascular endothelial growth factor (VEGF). In the early stage, elevated MMP‐9 cleaves GelMA microspheres, consuming MMP‐9 and releasing AMP to eradicate MRSA and mitigate infection‐driven inflammation. In the later stage, ROS degrades HA–PBA–PVA microspheres, quenching ROS while releasing VEGF to restore endothelial function and neovascularization. In vitro, the system shows stimuli‐responsive release, potent antibacterial activity, ROS scavenging, and improved endothelial migration and tube formation under oxidative stress. In a streptozotocin‐induced diabetic rat model with MRSA‐infected full‐thickness wounds, the dual‐microsphere hydrogel accelerates closure, reduces bacterial burden and inflammation, enhances collagen deposition and mature vessel formation, and shows no systemic toxicity. This work demonstrates a translational, stage‐matched strategy for regulating infected diabetic wounds.