Aging and cellular senescence are central to the pathogenesis of many chronic lung diseases, including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea (OSA), asthma, bronchiectasis, and lung cancer. Emerging evidence highlights extracellular vesicles (EVs) as important mediators connecting senescent cells to disease progression. Senescent cells adopt a senescence-associated secretory phenotype (SASP) that includes cytokines, chemokines, growth factors, and EVs, which can propagate deleterious signals to surrounding cells and tissues.
EVs are membrane-bound particles released by cells and encompass several subtypes distinguished by size and biogenesis. Exosomes (approximately 30–100 nm) originate from multivesicular bodies, microvesicles (about 100–1000 nm) bud directly from the plasma membrane, and apoptotic bodies (roughly 500 nm–5 μm) arise from apoptotic cells. EVs transport diverse cargo—nucleic acids (including microRNAs and circular RNAs), proteins, and lipids—that reflect the physiological or pathological state of the releasing cell. Their capacity to move between cells and tissues situates EVs as key players in intercellular communication in aging and disease.
EVs from senescent cells carry molecular components that have been implicated in promoting inflammation, fibrosis, tissue remodeling, and further cellular senescence. Specific microRNAs identified in EVs linked to lung disease include miR-21, miR-34a, and miR-570-3p. In addition to miRNAs, EVs convey proteins and other RNA species (for example, circular RNAs and piRNAs) that can influence processes such as extracellular matrix remodeling, matrix metalloproteinase activity, and signaling pathways (for example, MAPK, JAK/STAT) relevant to lung pathology.
Senescent-cell markers associated with EV-related signaling include increased senescence-associated β-galactosidase (SA-β-gal) activity, upregulation of cyclin-dependent kinase inhibitors p16 and p21, and elevated reactive oxygen species (ROS). EV cargo can induce telomere shortening, DNA damage responses, oxidative stress, and cell cycle arrest in recipient cells, thereby amplifying tissue-level senescence.
Multiple pulmonary cell types secrete EVs that participate in lung senescence and disease. These include airway and alveolar epithelial cells, fibroblasts, macrophages, neutrophils, endothelial cells, and airway smooth muscle cells. EVs released by these cells contain cell type–specific cargo that can act on neighboring epithelial cells, fibroblasts, immune cells, or endothelial cells to promote chronic inflammation, impaired repair, epithelial–mesenchymal transition, and fibrosis.
Figure-based summaries indicate that EV-mediated mechanisms relevant to chronic lung disease include promotion of inflammatory signaling, induction of profibrotic pathways, modulation of matrix remodeling (for example, via MMP-9), and interference with normal tissue repair. The precise contribution of individual EV components across different recipient cell types remains incompletely characterized.
EVs have been implicated in the pathogenesis and progression of a spectrum of chronic lung conditions where senescence is important. In COPD, EVs contribute to fibrosis, inflammation, impaired repair, and cellular senescence, and can be released in response to stressors such as cigarette smoke. In IPF and other fibrotic lung disorders, EV cargo can promote fibroblast activation and extracellular matrix deposition. In inflammatory airway diseases such as asthma and in bronchiectasis, EVs influence immune cell recruitment and activation. In obstructive sleep apnea, intermittent hypoxia–related EV signaling may contribute to vascular and inflammatory changes. EVs also play roles in the tumor microenvironment in lung cancer by modulating immune responses and facilitating tissue remodeling.
Across these diseases, EVs can have dual roles: promoting pathogenic processes (inflammation, fibrosis, senescence propagation) while also carrying molecules with potential anti-inflammatory or reparative effects, depending on cell of origin and cargo composition.
Because EVs reflect the state of their parent cells and can modulate recipient-cell behavior, they are under investigation as potential biomarkers and therapeutic agents. Identified miRNAs and proteins in EVs may serve as diagnostic or prognostic markers for disease activity or progression. Therapeutically, engineered EVs or EV-based delivery platforms (including nanotechnology approaches) have been explored experimentally to target inflammation, modulate immune responses, and enhance tissue repair. These strategies aim to leverage EVs for targeted drug delivery or to deliver beneficial cargo while minimizing off-target effects.
However, translation to clinical use requires careful evaluation of safety, potency, dosing, and delivery strategies.
Key limitations highlighted include the need to standardize EV isolation and characterization methods across studies to ensure reproducibility and comparability. The biological mechanisms by which specific EV components act on different pulmonary cell types remain incompletely understood; many roles are underexplored. Clinical translation demands rigorous preclinical safety assessment and well-designed clinical trials to verify the efficacy and safety of EV-based diagnostics and therapeutics.
Future research priorities include defining the causal roles of defined EV cargo in disease phenotypes, mapping cell type–specific EV signaling networks in the lung, improving EV manufacturing and characterization standards, and conducting clinical studies to evaluate therapeutic EVs or EV-modulating interventions.
EVs released by senescent cells are central mediators connecting aging processes to chronic lung disease pathogenesis. Through their cargo of miRNAs, proteins, and other molecules, EVs promote inflammation, fibrosis, tissue remodeling, and propagation of senescence across multiple pulmonary cell types. While EVs hold promise as biomarkers and therapeutic delivery vehicles, further mechanistic work, methodological standardization, and clinical validation are required before EV-based approaches can be widely adopted in patient care.