Engineering the airway microenvironment for functional tracheal regeneration -from structural substitution to...

Despite decades of efforts in long-segment tracheal reconstruction spanning synthetic prostheses, decellularized grafts, and tissue-engineered constructs, clinical outcomes have been limited by the convergence of multiple biological barriers. Initial injury and postoperative oxidative stress, infection, impaired epithelialization, and insufficient vascularization collectively create a hostile microenvironment that undermines graft integration and long-term airway function. In this context, a MXene@Cu-MOF/GelMA construct has been described as strategically engineered to address these interconnected challenges. MXene-based nanomaterials offer unique physicochemical properties, including high surface area and redox activity, enabling reactive oxygen species (ROS) scavenging and modulation of microenvironmental oxidative stress. The incorporation of Cu-based metal-organic frameworks (Cu-MOFs) introduces antimicrobial functionality, leveraging copper's well-established bactericidal effects while also contributing to angiogenic signaling pathways. When integrated within a GelMA hydrogel matrix, the resulting composite provides a structurally adaptable scaffold with tunable mechanical properties that can conform to the dynamic airway environment. An important and forward-looking implication of this work is the potential to integrate biologically active therapeutics into the MXene@Cu-MOF/GelMA platform. The physicochemical properties of MXene-based materials, combined with the porous architecture of GelMA hydrogels, make them well-suited for loading and controlled release of proteins, peptides, or nucleic acid-based agents. One particularly promising future candidate is MG53 (TRIM72), a membrane repair protein and circulating myokine with well-documented roles in cell membrane resealing, anti-inflammatory signaling, and tissue protection. MG53 has demonstrated therapeutic efficacy in multiple models of epithelial and endothelial injury, where it promotes rapid repair of membrane disruption and limits secondary inflammatory damage. In the setting of tracheal reconstruction, local delivery of MG53 may enhance epithelial barrier restoration, reduce leakage-induced inflammation, and support mucociliary function. Integration of MG53 into the MXene@Cu-MOF/GelMA scaffold could therefore provide a multimodal therapeutic strategy, combining structural support, redox regulation, antimicrobial activity, and active tissue repair. Moreover, the potential for sustained and localized delivery may overcome limitations associated with systemic administration, including rapid clearance and off-target effects. Beyond MG53, this platform could be adapted or combined with other emerging techniques to deliver a range of biologics, including pro-angiogenic factors (e.g., VEGF), anti-fibrotic agents, or immune modulators, further expanding its therapeutic versatility. Long-segment tracheal reconstruction remains an unresolved challenge in translational regenerative medicine. Despite decades of efforts spanning synthetic prostheses, decellularized grafts, and tissue-engineered constructs, clinical outcomes remain limited by converging biological barriers. Initial injury, postoperative oxidative stress, infection, impaired epithelialization, and insufficient vascularization collectively create a hostile microenvironment that undermines graft integration and long-term airway function.