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Here we use AMD patient\u2010specific RPE cells with the Complement Factor H Y402H high\u2010risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi\u2010omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co\u2010expressing retinal progenitor cell markers Pax6\/Vsx2, suggesting injury\u2010induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.<\/jats:p>","DOI":"10.1002\/jev2.12295","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:37:05Z","timestamp":1671669425000},"source":"Crossref","is-referenced-by-count":40,"title":["Retinal pigment epithelium extracellular vesicles are potent inducers of age\u2010related macular degeneration disease phenotype in the outer retina"],"prefix":"10.1002","volume":"11","author":[{"given":"Marzena","family":"Kurzawa\u2010Akanbi","sequence":"first","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences Newcastle University  Newcastle upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip","family":"Whitfield","sequence":"additional","affiliation":[{"name":"Glasgow Polyomics and Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences 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