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Extracellular vesicles (EVs), derived from allogeneic stem cells, have shown potential for modulating proinflammatory immunity. Among these, placental\u2010derived EVs (PEVs) are emerging as candidates for immune\u2010mediated inflammatory disorders due to their role in establishing maternal immune tolerance. However, their applicability beyond pregnancy remains limited by key translational barriers, including the lack of a standardized and scalable source system and need to demonstrate immunomodulatory activity in non\u2010pregnancy allogeneic contexts. In this study, we identify extravillous trophoblasts (EVTs), which play critical role in early placental development, as key source of immunoregulatory PEVs. To overcome donor variability, we employed the HIPEC cell model as established surrogate for primary EVTs and assessed the effects of their derived EVs (EVT\u2010EVs) on circulating monocytes, pivotal mediators of inflammatory responses. High\u2010dimensional molecular profiling revealed that EVT\u2010EVs, similar to EVs derived from first\u2010trimester primary human trophoblast, carry a distinctive anti\u2010inflammatory signature, including a unique miRNA repertoire enriched in immunoregulatory pathways. Integrated proteomic and lipidomic analyses demonstrated that EVT\u2010EVs induce coordinated functional reprograming of monocytes toward an immunomodulatory, inflammation\u2010resolving phenotype. Notably, EVT\u2010EVs also modulated the inflammatory bias of monocytes from patients with recessive dystrophic epidermolysis bullosa (RDEB), a genetic disorder characterized by chronic inflammation, thereby promoting restoration of immune balance. Collectively, these findings identify EVT\u2010EVs as a scalable, off\u2010the\u2010shelf platform with high translational potential for the treatment of chronic inflammatory diseases.<\/jats:p>","DOI":"10.1002\/jev2.70315","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:27:56Z","timestamp":1790256476000},"source":"Crossref","is-referenced-by-count":0,"title":["Trophoblast Extracellular Vesicles Rewire Immunity: A Symptom\u2010Relief Avenue for Recessive Dystrophic Epidermolysis Bullosa"],"prefix":"10.1002","volume":"15","author":[{"given":"Nell","family":"Hirt","sequence":"first","affiliation":[{"name":"Saint Louis Research Institute Saint\u2010Louis Hospital University of Paris INSERM CNRS, IRSL  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enzo","family":"Manchon","sequence":"additional","affiliation":[{"name":"Saint Louis Research Institute Saint\u2010Louis Hospital University of Paris INSERM CNRS, IRSL  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Wu","sequence":"additional","affiliation":[{"name":"Infinity\u2013Institute for Infectious and Inflammatory Diseases University of Toulouse CNRS INSERM  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helene Le","family":"Buanec","sequence":"additional","affiliation":[{"name":"Saint Louis Research Institute Saint\u2010Louis Hospital University of Paris INSERM CNRS, IRSL  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Bataille","sequence":"additional","affiliation":[{"name":"AP\u2010HP Department of Dermatology Saint\u2010Louis Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Bourrat","sequence":"additional","affiliation":[{"name":"AP\u2010HP Department of Dermatology Saint\u2010Louis Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010David","family":"Bouaziz","sequence":"additional","affiliation":[{"name":"Saint Louis Research Institute Saint\u2010Louis Hospital University of Paris INSERM CNRS, IRSL  Paris France"},{"name":"AP\u2010HP Department of Dermatology Saint\u2010Louis Hospital  Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4809-7836","authenticated-orcid":false,"given":"Nabila","family":"Jabrane\u2010Ferrat","sequence":"additional","affiliation":[{"name":"Infinity\u2013Institute for Infectious and Inflammatory Diseases University of Toulouse CNRS INSERM  Toulouse France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reem","family":"Al\u2010Daccak","sequence":"additional","affiliation":[{"name":"Saint Louis Research Institute Saint\u2010Louis Hospital University of Paris INSERM CNRS, IRSL  Paris 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