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We developed a non\u2010invasive post\u2010loading method to encapsulate macromolecules in EVs using our proprietary ionic lipid base (ILB), which enables electrostatically driver hybridisation without disrupting EV structure. Using EVs isolated from bovine milk and adipocyte\u2010derived mesenchymal stem cell culture medium, hybrid\u2010EVs (H\u2010EV) with different ILB contents encapsulating protein or nucleic acid molecules for delivery were produced in a reproducible manner. The H\u2010EV retained EV surface markers comparable to those of native EVs after preparation. After cellular uptake, the encapsulated molecules escaped from endosomes into the cytoplasm and exhibited intended functions. In an experiment using SH\u2010SY5Y neuroblastoma cells in which \u03b1\u2010synuclein (\u03b1Syn) aggregation was induced, the introduction of H\u2010EV encapsulating anti\u2010\u03b1Syn antibodies (Abs) significantly suppressed \u03b1Syn aggregation. Furthermore, delivery of anti\u2010phospho\u2010AKT Abs using H\u2010EV promoted caspase 3\/7 activity and cell apoptosis. Intravenous administration of H\u2010EV encapsulating a model Ab into mice resulted in detectable Ab signals in the cerebral cortex, cerebellum, hippocampus and other cells associated with neurodegenerative diseases within 24\u00a0h, as assessed by ex vivo imaging. H\u2010EV enabled loading of various molecules and their targeted transport to specific organs and the cytoplasm, highlighting their potential as a versatile platform for Ab therapies targeting intracellular proteins.<\/jats:p>","DOI":"10.1002\/jex2.70125","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:35:27Z","timestamp":1773758127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Macromolecule\u2010Loaded Hybrid Extracellular Vesicles via Ionic Lipid\u2013Based Post\u2010Loading for Intracellular Delivery: Functional Evaluation for Neurodegenerative Therapy"],"prefix":"10.1002","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4368-7508","authenticated-orcid":false,"given":"Lin","family":"Cui","sequence":"first","affiliation":[{"name":"NOVIGO Pharma Inc.  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