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Here, we developed an EV\u2010liposome hybrid vesicle formulation (NIN@SV) for inhalable delivery of nintedanib and identified a composition\u2010dependent balance between EV\u2010derived biological functionality and aerosol robustness. An optimized EV protein:NIN@LP lipid mass ratio of 3:7 enhanced mucus penetration and cellular association while minimizing post\u2010nebulization size drift and preserving aerodynamic performance. Density\u2010gradient fractionation and physical\u2010mixture controls supported the formation of a hybrid vesicle\u2010enriched population rather than simple coexistence of unfused EVs and liposomes. In parallel, FRET\u2010assisted membrane\u2010proximity analysis, calibrated using disruption controls, indicated improved resistance of NIN@SV to aerosol\u2010induced membrane perturbation. Functionally, NIN@SV enhanced formulation\u2010associated cellular association, prolonged pulmonary retention, and attenuated bleomycin\u2010induced pulmonary fibrosis under the tested nominal inhaled dosing regimen. Mechanistically, NIN@SV suppressed fibroblast activation and attenuated pro\u2010fibrotic macrophage\u2010associated features. Together, these findings support an aerosol\u2010resilient EV\u2010liposome membrane\u2010engineering strategy and provide a practical design rationale for inhalable hybrid vesicles in pulmonary drug delivery.<\/jats:p>","DOI":"10.1002\/adhm.71647","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T10:39:19Z","timestamp":1787827159000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineering Aerosol\u2010Resilient EV\u2010Liposome Hybrid Vesicles for Inhalable Nintedanib Delivery in Pulmonary Fibrosis"],"prefix":"10.1002","volume":"15","author":[{"given":"Xin","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Fudan University. Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Fudan University. Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6074-4207","authenticated-orcid":false,"given":"Jing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Fudan University. Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengkai","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Fudan University. Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Bian","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics School of Pharmacy Fudan University. 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