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The concept of ferrous\u2010supply regeneration, inspired by electro\u2010Fenton technology, has also gained interest as a non\u2010apoptotic approach to induce ferroptosis. However, integrating both strategies into a single lipid nanoparticle (LNP) remains challenging. To address this, we developed ALSF, a novel LNP in which DSPC is replaced with arachidonic acid (AA) to enable co\u2010delivery of Glutathione Peroxidase 4\u2010siRNA (GPX4\u2010siRNA) and Fe\n                    <jats:sup>3<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    . ALSF facilitates acid\u2010 and H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    \u2010dependent iron recycling, continuously regenerating Fe\n                    <jats:sup>2<\/jats:sup>\n                    <jats:sup>+<\/jats:sup>\n                    to drive ROS production, while GPX4\u2010siRNA silences GPX4 to induce lipid peroxidation (LPO) and ferroptosis. Elevated H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    levels in cancer cells promote selective iron recycling, lysosomal disruption, and siRNA escape, enabling effective gene knockdown at lower doses. In vivo, ALSF suppressed tumor growth in a C918 xenograft model with favorable biosafety. This study is the first to integrate a ferrous\u2010supply\u2010regeneration system with siRNA into a single LNP platform, offering a selective ferroptosis\u2010inducing strategy for ocular cancers and other ferroptosis\u2010sensitive malignancies.\n                  <\/jats:p>","DOI":"10.1002\/smll.74925","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T07:53:01Z","timestamp":1785397981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Ferrous\u2010Supply\u2010Regenerating Lipid Nanoparticle Integrating RNAi Induces Ferroptosis for Cancer Therapy"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5529-9455","authenticated-orcid":false,"given":"Dun","family":"Hu","sequence":"first","affiliation":[{"name":"College of Chemistry and Chemical Engineering Central South University  Hunan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun\u2010Hua","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Chemistry and Chemical Engineering Central South University  Hunan People's Republic of China"},{"name":"R&amp;D, Rayzon Medical Technology Co., Ltd.  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