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While hybrid exosome strategies combining multiple cell components can address this, current methods rely on native exosome extraction and drug loading, suffering from low yield and encapsulation efficiency. We developed a biological origin\u2010based hybrid biomimetic exosome (BOB\u2010HBE) platform that synthetically assembles exosomes using parent cell\u2010derived components through a water\/oil\/water emulsion method, overcoming production bottlenecks. For high\u2010altitude pulmonary edema (HAPE) treatment, we engineered hybrid exosomes combining: (1) vascular endothelial cell membranes for lung targeting, (2) mesenchymal stem cell factors for regeneration, and (3) eNOS\u2010encoding plasmid DNA to restore nitric oxide signaling. The BOB\u2010HBE platform achieved &gt;150\u2010fold higher production yield than natural exosome isolation while enhancing pulmonary endothelial specificity. In HAPE models, these hybrid exosomes demonstrated triple therapeutic effects: restoring NO bioavailability, inhibiting pathogenic HIF\u20101\u03b1\/TGF\/Smad1\/5 signaling, and preventing endothelial\u2010mesenchymal transition and vascular remodeling. Consequently, they significantly attenuated HAPE progression by addressing both molecular pathways and tissue\u2010level pathology. This study establishes a scalable platform for constructing multifunctional exosome mimetics that maintain native exosome advantages while solving key production challenges. The cell\u2010origin\u2010informed design strategy offers a versatile approach for targeted therapy in pulmonary and vascular disorders, with potential clinical translation advantages.<\/jats:p>","DOI":"10.1002\/adhm.202504014","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T14:12:32Z","timestamp":1773843152000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Scalable Production of Multi\u2010Source Hybrid Biomimetic Exosomes Co\u2010Loaded with Therapeutic Plasmids for Treatment of High\u2010Altitude Pulmonary Edema"],"prefix":"10.1002","volume":"15","author":[{"given":"Sujia","family":"Si","sequence":"first","affiliation":[{"name":"School of Pharmacy Xuzhou Medical University  Xuzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Xuzhou Medical University  Xuzhou 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