Cascade-Responsive MXene@Cu-MOF Heterostructure Integrates Antioxidant Activity, Infection Control, and...

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 Ti₃C₂T_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 Cu²⁺ release, while near-infrared light accelerates MOF decomposition to deliver on-demand Cu²⁺ bursts, enhancing antibacterial efficacy through photothermal heating; 3) Sustained low-dose Cu²⁺ 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.