Multiplexed self-adaptable Janus hydrogels rescue epithelial malfunction to promote complete trachea repair.

Epithelial malfunction rescue is the decisive step involved in complete trachea repair; however, this step remains challenging due to the harsh tracheal environment and unclear pathogenesis, which still made current bioengineered trachea transplants receive fatal complications. Herein, bacterial infection-induced neutrophilic oxidative stress imbalance and epithelial stemness loss were identified as the pathogenic factors. Targeting pathogenesis, multiplexed hydrogels with adhesive and anti-fouling Janus sides, anti-swelling and anti-bacteria properties are constructed to adapt in mucous and causative agent-rich trachea environments. In two epithelial injury models and two tracheal transplantation-related epithelial deficiency models, the hydrogels blockade oxidative stress-innate immune cascade axis, reactivate epithelial mucociliary regenerative ability to rescue epithelial malfunction with stenosis-free mucociliary epithelium regeneration. Importantly, the versatility of hydrogel is validated via its integration with routine bioengineered vascular and cartilage transplants, wherein the regenerated pseudostratification epithelium, cartilage and vascularization resemble native-like trachea, resulting in the complete tracheal repair including structure and respiratory function reinvigoration. Our research provides insights into epithelial interface diseases and guides related biomaterials design.