Abstract

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by irreversible damage to the airways, alveoli, and pulmonary microvasculature. As the third leading cause of death worldwide, COPD remains without effective therapies to halt or reverse structural lung damage. Regenerative approaches utilizing lung-resident stem/progenitor cells present a promising therapeutic strategy; however, the underlying molecular mechanisms remain incompletely understood. This study aimed to investigate whether the reparative effects of airway basal stem cells (BCs) in COPD are mediated, at least in part, through paracrine mechanisms involving BC-derived extracellular vesicles (BC-EVs). Methods Lineage-tracing analysis was performed to determine the involvement of endogenous BCs in epithelial repair following COPD-related lung injury. Airway BCs were isolated, expanded ex vivo , and transplanted into elastase-induced COPD mouse models, followed by histological evaluation and RNA-seq–based transcriptomic analysis to assess regenerative efficacy. For mechanistic studies, BC-EVs were collected from cultured BCs and characterized using transmission electron microscopy, Nano-Flow Cytometry, and Western blotting. Their biological activity was assessed by CCK-8 and tube formation assays. BC-EVs were delivered to COPD mice via nebulization, with in vivo imaging tracking distribution. Therapeutic efficacy was evaluated by histology and arterial blood gas analysis. Proteomic profiling was conducted to elucidate the molecular mechanisms underlying BC-EV–mediated repair. Results Lineage tracing revealed active participation of endogenous BCs in epithelial repair. Transplantation of ex vivo –expanded BCs significantly restored alveolar architecture and alleviated pathological manifestations in COPD mice. Nebulized BC-EVs reproduced these benefits, promoting angiogenesis, enhancing epithelial repair, and improving lung function. Proteomic ana