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Lysosomal impairments cause iron dysregulation and initiate ferroptosis, which potentially contribute to ionizing radiation\u2010induced tissue damages. Here, the role of intercellular lysosomal regulation in governing iron homeostasis and protecting against ferroptosis is investigated in models of stem cell aggregation and mandibular regeneration post\u2010irradiation. Lysosomes are discovered to accumulate in specific regions within multi\u2010stem cell aggregates and regulate cell aggregate formation based on iron control, which is occurred through hypoxic signaling\u2010driven lysosomal redistribution mediated by extracellular vesicles. These vesicles exhibit lysosomal features and possess iron\u2010regulating properties, which rescue lysosomal defects to restore iron homeostasis and mitigate ferroptosis in recipient endothelial cells against the irradiation challenge. Based on lysosomal regulation and anti\u2010ferroptosis, these cell aggregate\u2010released extracellular vesicles (CA\u2010EVs) stimulate the growth of CD31\n                    <jats:sup>+<\/jats:sup>\n                    endomucin\n                    <jats:sup>+<\/jats:sup>\n                    specialized vessels despite irradiation both in vitro and in vivo, which further promote bone regeneration of post\u2010irradiation mandibular defect. These findings highlight the potential of taking CA\u2010EVs as natural therapeutic agents to safeguard lysosomal function, modulate iron metabolism, and protect against ferroptosis, paving an avenue for combating post\u2010irradiation endothelial injuries and enhancing tissue regeneration.\n                  <\/jats:p>","DOI":"10.1002\/advs.202505070","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T05:25:32Z","timestamp":1750656332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Lysosome\u2010Featured Cell Aggregate\u2010Released Extracellular Vesicles Regulate Iron Homeostasis and Alleviate Post\u2010Irradiation Endothelial Ferroptosis for Mandibular Regeneration"],"prefix":"10.1002","volume":"12","author":[{"given":"Yuan\u2010Yuan","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration 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