Dynamic Molecular Engineering Occluder for Spatiotemporally Adaptable Complex Tissue Repair

Tracheal fistula is a life-threatening disorder for which no current therapy can simultaneously provide immediate airway rescue and long-term functional regeneration. Here we report a completely biodegradable, cell-free, off-the-shelf therapeutic construct that enables spatiotemporally matched repair by dynamically adapting to the evolving physiological demands of healing. The system integrates dynamic covalent and non-covalent interactions with distinct response timescales across spatially stratified layers, thereby supporting acute functional substitution, intermediate regenerative integration, and late-stage tissue replacement within a single intervention. In rabbit models, the construct achieved immediate airtight sealing and restoration of ventilation, improved survival from 0% to 100%, and enabled native-like tracheal regeneration with ciliated epithelium. In head-to-head comparisons, it outperformed both clinical flap repair and tissue-engineered graft repair in functional epithelial reconstruction. In a goat model, it maintained airway patency under human-scale physiological conditions. These findings establish a clinically relevant strategy for tracheal fistula repair and show that dynamically adaptive materials can bridge the gap between acute intervention and functional regeneration.