Extracellular vesicle-based delivery to airway basal cells for durable gene therapy in cystic fibrosis

Airway basal cells are an appealing target for durable genetic therapy in cystic fibrosis because they are long-lived stem/progenitor cells that maintain and regenerate the pseudostratified airway epithelium. Correcting this compartment could, in principle, enable sustained restoration of CFTR function in differentiated epithelial lineages. However, selective in vivo targeting of basal cells remains challenging, owing to their position beneath the luminal epithelium and disease-associated remodeling of the cystic fibrosis airway. This Review examines the biological rationale for targeting airway basal cells in cystic fibrosis, with particular emphasis on the identification of surface markers that may permit selective delivery. We further survey peptide ligands with reported sequences for selected markers and consider extracellular vesicles as potential carriers for pulmonary delivery of genome-editing cargo to airway basal cells. Together, these considerations define the principal opportunities and current constraints of strategies aimed at targeting airway basal cells for durable cystic fibrosis therapy.