Small RNA Profiles of Serum-Derived Extracellular Vesicles in the Comorbid Condition of Frailty and Obstructive Pulmonary Disease: An Observational, Cross-Sectional Study

Frailty is increasingly recognized as a systemic complication in patients with obstructive pulmonary diseases (OPDs), yet its molecular basis remains unclear. Extracellular vesicles (EVs), which transport small RNAs, may offer mechanistic insight into this comorbidity. This study investigated the association between serum-derived EV small RNAs and frailty in OPD. Sixty-eight patients with OPD were enrolled, and EVs isolated from 29 patients (13 with chronic obstructive pulmonary disease [COPD], four with COPD and asthma, and 12 with asthma; median age 72 years) were analyzed. Based on the Kihon Checklist, patients were classified as frail (<i>n</i> = 11) or non-frail (<i>n</i> = 18). Small RNA sequencing and differential expression analyses were conducted, followed by age-adjusted correlation with physical factors and Ingenuity Pathway Analysis (IPA). A total of 108 small RNAs were differentially expressed between frail and non-frail groups (<i>p</i> < 0.05, fold change < 0.8 or >1.2). IPA linked these RNAs to lung fibrosis and transforming growth factor-beta (TGF-β) signaling pathways. Eleven small RNAs correlated with lower limb strength, and three-miR-125b-5p, miR-369-3p, and miR-615-3p-emerged as key candidates associated with frailty. These findings suggest that EV-derived small RNAs may contribute to frailty development in OPD through TGF-β-related molecular mechanisms.