Removal of ferroptosis barrier mediated by nanoengineering platform for the treatment of tumor lymphatic metastasis

Malignant cells usually metastasize locally through the lymphatic system before systematically through the blood. Importantly, malignant cell membrane after lymphatic metastasis has a higher proportion of oleic acid (OA), a monounsaturated fatty acid, which has been proven to protect malignant cells from ferroptosis after entering the blood with high oxidative stress and promote the occurrence of metastatic tumors. However, no effective strategy has been developed to remove OA on the malignant cell membrane after lymphatic metastases so far. Malignant cells after lymphatic metastasis often upregulate their ferroptosis defense systems, including GPX4-GSH system and FSP1-CoQH2 system, to achieve ferroptosis evasion. Recently, chemodynamic therapy (CDT) has been widely used in preclinical research of malignant tumor treatment with satisfactory results. However, whether CDT can be used to remove the ferroptosis barrier including OA and ferroptosis defense systems so as to induce ferroptosis of tumor cells has not been confirmed. Herein, for the first time, we show that CDT nanoengineering platform (NEP) can remove ferroptosis-inhibitory OA and inactivate ferroptosis defense system to clean the path of ferroptosis therapy for tumor lymphatic metastasis. This strategy implies a general principle for the treatment of tumor metastasis by targeted ferroptosis, which may boost the research and clinical translation of ferroptosis as a promising therapeutic pattern for tumor metastasis treatment.