Decoding the role of extracellular vesicles in pathogenesis of cystic fibrosis

Intercellular communication is a critical process that ensures cooperation between distinct cell types and maintains homeostasis. In the past decades, extracellular vesicles (EVs) have been recognized as key components in cell-to-cell communication. These EVs carry multiple factors such as active enzymes, metabolites, nucleic acids and surface molecules that can alter the behavior of recipient cells. Thus, the role of EVs in exacerbating disease pathology by transporting inflammatory mediators, and other molecular signals that contribute to chronic inflammation and immune dysregulation in various diseases including cystic fibrosis (CF) is well documented.

CF is a genetic disorder characterized by chronic inflammation and persistent infections, primarily affecting the respiratory system. This review explores the multifaceted roles of EVs in CF lung disease, focusing on their biogenesis, cargo, and contributions to disease progression. It is well known that CF results from mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, leading to defective ion transport, thick mucus secretion, and a propensity for bacterial infections. However, it has been observed that EVs derived from CF patients carry altered molecular cargo, including proteins, lipids, RNA, and DNA, which can exacerbate these conditions by promoting inflammation, and modulating immune responses. Beyond their pathogenic roles, EVs also hold significant therapeutic potential. Their natural ability to transfer bioactive molecules positions them as promising vectors for delivering therapeutic agents, such as gene therapy constructs and anti-inflammatory compounds. Accordingly, a study has shown that these EVs can act as a carrier molecule for transport of functional CFTR mRNA, helping to restore proper chloride ion channel function by correcting defective CFTR proteins in affected cells.

This review aims to summarize the role of EVs and their molecular cargo in pathogenesis of CF lung disease via modulation of intracellular signaling leading to persistent inflammation and increased disease severity. We also explored the mechanisms of EV biogenesis, cargo selection, and their effects on recipient cells which may provide novel insights into CF pathogenesis and open new avenues for EV-based therapies aimed at improving disease management.