Stage‐Adaptive Bilayer Hydrogel Coordinates Photodynamic Antibacterial Therapy with Engineered Extracellular Vesicle–Mediated Immunomodulation in Infected Diabetic Wounds

During the early phase of treatment, infected diabetic wounds require rapid bacterial control, whereas subsequent healing benefits from relief of persistent oxidative stress and inflammation, resulting in distinct and partly opposing redox demands over time. We therefore developed a stage-adaptive bilayer hydrogel that separates photodynamic antibacterial therapy from engineered small extracellular vesicle (sEV) delivery. The wound-contacting layer contains chlorin e6 (Ce6), while the ROS-responsive upper layer scavenges ROS and retains miR-146a-enriched sEVs carrying a human CD64-recognition module. The bilayer architecture limited premature release of sEV-associated particles during photodynamic treatment but allowed substantial release thereafter, with key vesicle-associated features preserved after irradiation. In human macrophages, engineered sEVs increased intracellular miR-146a, reduced IRAK1 abundance and NF-κB p65 phosphorylation, decreased CD86, and increased CD206. These effects were partly weakened by CD64 blockade. In infected diabetic wounds, Bil-Gel@miR-sEVs reduced bacterial burden and oxidative stress, suppressed IRAK1/NF-κB-associated inflammatory signaling, shifted macrophage-associated markers toward a repair-associated pattern, and improved epithelial, vascular, and matrix reconstruction. This bilayer design therefore links early infection control with later immunoregulation and tissue repair within one biomaterial.