Overcoming AZD9291 Resistance and Metastasis of NSCLC via Ferroptosis and Multitarget Interference by Nanocatalytic Sensitizer Plus AHP‐DRI‐12

Abstract The acquired resistance to Osimertinib (AZD9291) greatly limits the clinical benefit of patients with non‐small cell lung cancer (NSCLC), whereas AZD9291‐resistant NSCLCs are prone to metastasis. 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)–Fe(II), si‐OTUB2, ASO‐MALAT1, resulting in efficient inhibition of tumor growth and metastasis of NSCLC by synergizing with AHP‐DRI‐12, an anti‐hematogenous metastasis inhibitor by blocking the amyloid precursor protein (APP)/death receptor 6 (DR6) interaction designed by our lab. Fe 2+ released from Vc–Fe(II) generates cytotoxic hydroxyl radicals (•OH) through Fenton reaction. Subsequently, glutathione peroxidase 4 (GPX4) is consumed to sensitize AZD9291‐resistant NSCLCs with high mesenchymal state to ferroptosis due to the glutathione (GSH) depletion caused by Vc/dehydroascorbic acid (DHA) conversion. By screening NSCLC patients’ samples, metastasis‐related targets (OTUB2, LncRNA MALAT1) are confirmed. Accordingly, the dual‐target knockdown plus AHP‐DRI‐12 significantly suppresses the metastasis of AZD9291‐resistant NSCLC. Such modality leads to 91.39% tumor inhibition rate in patient‐derived xenograft (PDX) models. Collectively, this study highlights the vulnerability to ferroptosis of AZD9291‐resistant tumors and confirms the potential of this nanocatalytic‐medicine‐based modality to overcome critical AZD9291 resistance and inhibit metastasis of NSCLC simultaneously.