Prevalence and determinants of social frailty among community-dwelling empty-nest older adults in China.

MSCs have been used for diverse clinical applications in the treatment of autoimmune diseases due to their immunomodulation potential (). EVs are small vesicles that can be secreted by various cell types. Owing to their small size with an average diameter of approximately 30~150 nm, they can effectively bypass physiological barriers and reach the intended target tissues and serve as mediators of cell-to-cell communication (, ). Moreover, recent studies suggest that EVs secreted from MSCs are critical for mediating the biological functions of MSCs (). These EVs have emerged as important markers in liquid biopsies, offering significant potential for disease diagnosis, therapeutic interventions, and prognostic assessments (, ). The use of MSC-EVs is increasingly being considered as a cell-free therapy option. MSC-EVs offer potential advantages over MSCs, including lower immunogenicity, easier storage and transport, making them attractive for clinical applications (). MSCs can modulate both adaptive and innate immunity, possessing the dual capacity to suppress immune cell activation and proliferation, while also promoting immune responses through pro-inflammatory factors and chemokines secretion (–). MSCs could improve the allergic airway disease by inhibiting the proliferation and function of dendritic cells (DC) which have an immunomodulatory effect, and which are differentiated into T cells and B cells (–). The intravenous injection of MSCs significantly reduced eosinophil infiltration in the nasal mucosa and lung tissue of allergic mouse models and improved the degree of airway hypersensitivity and allergic symptoms (–). The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has had a significant global impact on health. According to the World Health Organization (WHO), approximately 10% to 20% of COVID-19 patients experience persistent symptoms after acute COVID-19 infection (). Post-COVID condition (PCC) encompasses multiple adverse outcomes, including cardiovascular, type 2 diabetes (), cerebrovascular disease () and dozens of other symptoms across multiple organ systems () that may due to immune dysregulation (). Similar to typical respiratory infections such as the common cold or influenza, coughing stands out as a significant symptom of COVID-19 and has the potential to linger during the post-infection period, reflecting the virus's impact on the respiratory system. Research data suggests that up to 18% of patients develop a persistent cough after COVID-19 infection (). As the COVID-19 virus primarily invades the respiratory tract mucosa, causing local inflammatory response and airway hyperreactivity, the cough following COVID-19 infection tends to be more severe and persistent. Identifying safe and rapidly acting therapies for post-COVID chronic cough is of clinical importance. Furthermore, patients with chronic cough often seek antitussive therapies, but it is unclear whether these approaches are effective in managing cough in individuals recovering from COVID-19 (). MSC derived-EVs (MSC-EVs) have received much attention as a novel cell-free therapeutic strategy during this period. Studies have shown that MSC-EVs can exert therapeutic effects through various pathways including regulating immune response, inhibiting inflammatory response, and alleviating lung injury and inflammation (–). Additionally, MSC-EVs can also release multiple biologically active substances, such as cytokines and growth factors (, ). Multiple clinical trials on the treatment of lung diseases with MSC-EVs have been registered in the database. For example, a randomized, double-blind, placebo-controlled clinical trial named “A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia” () has been registered on . The trial shows a consecutive 5 days inhalation dose of clinical grade haMSC-Exos was feasible and well tolerated in seven COVID-19 patients, with no evidence of prespecified adverse events, immediate clinical instability, or dose-relevant toxicity at any of the doses tested (). Another clinical trial on nebulization therapy with MSC-derived EVs was conducted on seven patients with COVID-19 pneumonia (ChiCTR2000030261). Nebulization of MSC-derived EVs was found to be a safe and effective method, promoting absorption of pulmonary lesions and reducing hospitalization duration for mild cases of COVID-19 pneumonia (). Here, we propose a pilot study of nebulized 3D-cultured MSC-EVs for the treatment of chronic cough following COVID-19 infection. This exploratory trial aims to evaluate the safety and preliminary efficacy of this therapy, with a focus on rapid symptom relief and immunomodulatory trends. At the same time, this study is expected to provide initial evidence supporting the feasibility of MSC-EVs for post-COVID chronic cough and to inform the design of larger confirmatory trials.