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Although deferoxamine can effectively chelate iron, its clinical application is limited by poor membrane permeability, short half\u2010life, and lack of targeting capability. To overcome these challenges, we designed and synthesized a family of DFO\u2010bearing lipids by modifying the molecule with dual fatty acid chains of varying lengths, and co\u2010assembled them with auxiliary lipids via microfluidics to construct \u201ciron\u2010deprivation\u201d liposomes. Among them, the medium\u2010chain DFO\u2010C12\u2010liposomes exhibited the highest cellular uptake, iron\u2010deprivation efficiency, and anticancer activity in vitro, markedly depleting mitochondrial iron, disrupting Fe\u2013S cluster synthesis, suppressing mitochondrial respiration, and inducing autophagy. Furthermore, DFO\u2010C12\u2010liposomes efficiently coordinated Mn\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    via DFO\u2013Mn\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    chelation, providing MRI capability while inducing iron deprivation\u2013mediated ferroptosis. In addition, the iron\u2010deprivation liposomes can encapsulate anticancer drugs such as doxorubicin, leading to an enhanced antitumor effect through the combination of iron deprivation and chemotherapy for osteosarcoma treatment. In summary, the \u201ciron\u2010deprivation\u201d liposomes integrate iron chelation, imaging functionality, and chain\u2010length\u2010dependent cellular uptake into a versatile nanoplatform for regulating tumor iron homeostasis and achieving enhanced antitumor efficacy through multimodal therapeutic strategies.\n                  <\/jats:p>","DOI":"10.1002\/anie.5926794","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T03:48:04Z","timestamp":1788925684000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Iron\u2010Deprivation Liposomes for Cancer Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7811-4654","authenticated-orcid":false,"given":"Jia","family":"Ji","sequence":"first","affiliation":[{"name":"Shanghai Frontiers Science Center of Genome Editing and Cell Therapy Shanghai Key Laboratory of Regulatory Biology School of Life Sciences East 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