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It's challenging to overcome AZD9291 resistance and suppress metastasis of NSCLC simultaneously. Here, a nanocatalytic sensitizer (VF\/S\/A@CaP) is proposed to deliver Vitamin c (Vc)\u2013Fe(II), si\u2010OTUB2, ASO\u2010MALAT1, resulting in efficient inhibition of tumor growth and metastasis of NSCLC by synergizing with AHP\u2010DRI\u201012, an anti\u2010hematogenous metastasis inhibitor by blocking the amyloid precursor protein (APP)\/death receptor 6 (DR6) interaction designed by our\u00a0lab. Fe<jats:sup>2+<\/jats:sup> released from Vc\u2013Fe(II) generates cytotoxic hydroxyl radicals (\u2022OH) through Fenton reaction. Subsequently, glutathione peroxidase 4 (GPX4) is consumed to sensitize AZD9291\u2010resistant NSCLCs with high mesenchymal state to ferroptosis due to the glutathione (GSH) depletion caused by\u00a0Vc\/dehydroascorbic acid (DHA) conversion. By screening NSCLC patients\u2019 samples, metastasis\u2010related targets (OTUB2, LncRNA MALAT1) are confirmed. Accordingly, the dual\u2010target knockdown plus AHP\u2010DRI\u201012 significantly suppresses the metastasis of AZD9291\u2010resistant NSCLC. Such modality leads to 91.39% tumor inhibition rate in patient\u2010derived xenograft (PDX) models. Collectively, this study highlights the vulnerability to ferroptosis of AZD9291\u2010resistant tumors and confirms the potential of this nanocatalytic\u2010medicine\u2010based modality to overcome critical AZD9291 resistance and inhibit metastasis of NSCLC simultaneously.<\/jats:p>","DOI":"10.1002\/smll.202204133","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T13:40:29Z","timestamp":1669297229000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Overcoming AZD9291 Resistance and Metastasis of NSCLC via Ferroptosis and Multitarget Interference by Nanocatalytic Sensitizer Plus AHP\u2010DRI\u201012"],"prefix":"10.1002","volume":"19","author":[{"given":"Liting","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oncogenes and Related Genes Renji Hospital School of Biomedical Engineering Shanghai Jiao Tong University  Shanghai 200032 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