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We demonstrate here AAV serotype 6 (AAV6) associated with extracellular vesicles (EVs) and secreted from vector\u2010producing HEK\u2010293 cells during vector preparation (EVAAV6) as a safe and highly efficacious gene delivery platform for inhaled gene therapy applications. Specifically, we discovered that EVAAV6 provided markedly enhanced reporter transgene expression in mucus\u2010covered air\u2010liquid interface (ALI) cultures of primary human bronchial and nasal epithelial cells as well as in mouse lung airways compared to standard preparations of AAV6 alone. Of note, AAV6 has been previously shown to outperform other clinically tested AAV serotypes, including those approved by the FDA for treating non\u2010lung diseases, in transducing ALI cultures of primary human airway cells. We provide compelling experimental evidence that the superior performance of EVAAV6 is attributed to the ability of EV to facilitate mucus penetration and cellular entry\/transduction of AAV6. The tight and stable linkage between AAV6 and EVs appears essential to exploit the benefits of EVs given that a physical mixture of individually prepared EVs and AAV6 failed to mediate EV\u2010AAV6 interactions or to enhance gene transfer efficacy.<\/jats:p>","DOI":"10.1002\/jev2.12324","type":"journal-article","created":{"date-parts":[[2023,6,7]],"date-time":"2023-06-07T17:44:40Z","timestamp":1686159880000},"source":"Crossref","is-referenced-by-count":21,"title":["Extracellular vesicles enhance pulmonary transduction of stably associated adeno\u2010associated virus following intratracheal\u00a0administration"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6908-9638","authenticated-orcid":false,"given":"Gijung","family":"Kwak","sequence":"first","affiliation":[{"name":"Center for Nanomedicine at Wilmer Eye Institute Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Department of Ophthalmology Johns Hopkins University 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