Cascade‐Responsive MXene@Cu‐MOF Heterostructure Integrates Antioxidant Activity, Infection Control, and Vascularization for Tracheal Repair

ABSTRACT Extensive tracheal repair is limited by oxidative injury, infection, and insufficient vascularization with delayed cartilage maturation. We developed cascade‐responsive MXene@Cu‐MOF heterostructures within gelatin methacryloyl (GelMA) hydrogels to enable staged tracheal repair. Copper‐based metal‐organic framework (Cu‐MOF) nanocrystals grown in situ on ultrathin Ti ₃ C ₂ T _x MXene form an integrated 2D/3D heterointerface, preventing restacking and ensuring uniform “backpack” distribution on a photothermal skeleton. The platform acts in three stages: 1) MXene scavenges radicals, reducing oxidative stress and stabilizing the early environment; 2) Mild acidification triggers pH‐responsive Cu ²⁺ release, while near‐infrared light accelerates MOF decomposition to deliver on‐demand Cu ²⁺ bursts, enhancing antibacterial efficacy through photothermal heating; 3) Sustained low‐dose Cu ²⁺ promotes endothelial proliferation, migration, and tube formation with VEGF, eNOS, HIF‐1α, and FGF2 upregulation, supporting vascular ingrowth. Ring‐to‐tube–fabricated MXene@Cu‐MOF/GelMA tracheal constructs show robust proteoglycans, type II collagen, and biomechanical stiffness. In a rabbit extensive tracheal defect model, MXene@Cu‐MOF/GelMA tracheal grafts improve airway patency and survival, reduce infection and mucus impaction, and enhance epithelial, vascular, and cartilage regeneration. Bulk RNA‐seq confirms suppression of inflammatory pathways and enrichment of antibacterial, angiogenic, and chondrogenic programs. This cascade platform couples photothermal conversion with on‐demand ionic dosing to integrate antioxidant activity, infection control, and vascularization for clinically translatable tracheal repair.