Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by persistent airflow limitation and the loss of functional lung tissue. Prolonged exposure to harmful particles or gases, especially cigarette smoke (CS), is the primary risk factor for its development [1,2]. According to World Health Organization (WHO) predictions, by 2030, COPD will become the third leading cause of morbidity and mortality globally, imposing an enormous economic burden on individuals and human society [3]. Current available treatment methods for COPD primarily help to control symptoms and do not reverse lung damage or significantly improve the quality of life for these patients [4]. Therefore, there is a critical need for the development of therapies focused on repair and regeneration. In recent years, there has been increasing interest in the research of mesenchymal stem cells (MSC) and their derivatives as potential therapeutic agents for various respiratory diseases, including COPD [5,6].

MSCs are increasingly recognized as promising candidates for cell therapy and regenerative medicine due to their ability to regulate immune responses, suppress inflammation, promote tissue regeneration, and restore pulmonary dysfunction [7,8]. Extensive research has highlighted their therapeutic potential in respiratory diseases such as COPD, acute respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis, positioning them as strong contenders for lung injury regeneration [[9], [10], [11]]. Notably, the beneficial effects of MSCs are now attributed primarily to their secreted products, particularly extracellular vesicles (EVs). Exosomes, a subset of EVs, play a crucial role in mediating intercellular communication by delivering molecular cargo from donor cells to recipient cells. Due to the biocarrier properties similar to progenitor cells and the ability to retain regenerative characteristics, exosomes are considered potential alternatives to MSCs for treating various diseases [12]. For instance, human umbilical cord mesenchymal stem cell (hUC-MSC)-derived EVs effectively ameliorate by COPD-induced inflammation [13]. Moreover, the nebulization of platelet-derived exosomes can effectively deliver therapeutic cargo into the lungs, alleviating CS-induced pulmonary emphysema and reducing oxidative stress, inflammation, and alveolar epithelial cell apoptosis in preclinical models [14]. These findings underscore the therapeutic potential of exosomes in pulmonary diseases, though further preclinical studies are necessary to establish the safety and feasibility of exosome-based therapies for clinical application.

The significant pathological changes in COPD involve an irregular inflammatory pattern, airway and parenchymal remodeling, ultimately small airway fibrosis and obliteration [15]. Recent studies on smoking-related COPD further emphasize that epithelial–mesenchymal transition (EMT) plays a pivotal role in airway remodeling, fibrosis, and subsequent airflow obstruction, and may also contribute to the increased incidence of lung cancer [16,17]. EMT is a dynamic and reversible process in which epithelial cells lose their characteristic phenotypes (e.g., E-cadherin [E-cad], cytokeratin 19 [CK19]) and transition into mesenchymal-like cells (e.g., α-smooth muscle actin [α-SMA]). This process is increasingly recognized as a central pathological and physiological factor in the progression of both COPD and lung cancer [18,19]. Key signaling pathways involved in EMT include TGF-β, WNT, Notch, Twist, Snail, and Sonic Hedgehog [20]. While the WNT/β-catenin pathway is well-known for its critical role in embryonic development and maintaining homeostasis [21], growing evidence suggests that dysregulated activation of this pathway contributes to the pathogenesis of COPD. Carlier et al. demonstrated that the WNT/β-catenin pathway is activated in the proximal bronchial epithelium of COPD patients, highlighting its role in regulating epithelial homeostasis in the lungs, including epithelial de-differentiation, loss of polarity, barrier dysfunction, and EMT [22]. Moreover, in response to TGF-β1 stimulation, lung fibroblasts in COPD patients appear more predisposed to expressing EMT features in a Wnt/β-catenin-dependent manner [23]. β-catenin expression is upregulated in the airway walls of smokers and COPD patients, with its levels closely correlating with EMT activity and airway obstruction [24,25]. Therefore, targeting the Wnt/β-catenin pathway represents a promising therapeutic strategy to mitigate EMT induction caused by CS in COPD.

This study compared the therapeutic efficacy of nebulized versus intravenously administered bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in COPD rats, focusing on the mechanisms by which nebulized BMSC-Exos influence pulmonary tissue remodeling induced by CS and lipopolysaccharide (LPS). The results showed that nebulized BMSC-Exos significantly improved lung function, alleviated inflammation, and reduced fibrotic damage in COPD model rats. Furthermore, nebulized BMSC-Exos reversed EMT in COPD, which was likely related to the inhibition of the Wnt/β-catenin signaling pathway. These findings illustrated the potential of MSC-Exos inhalation as a noninvasive and effective therapeutic strategy for COPD.