EDTA-Mg Nano-Chelators Amplify Ferroptosis by Artificially Simulating the Epithelial-Mesenchymal Transition Process and Endogenous Iron Deprivation.

Epithelial-mesenchymal transition (EMT) is a key step in initiating tumor metastasis. Commonly, researchers focus on inhibiting EMT to prevent tumor metastasis. However, they ignore that tumor cells undergoing EMT are more vulnerable to disturbance from the external environment. Tumor cells in this period are a potential therapeutic target, yet precisely regulating the EMT of tumor cells remains a challenging problem to be solved. Here, based on metal chelation therapy, we propose a strategy of artificially mimicking EMT, integrating ferroptosis and immunotherapy to inhibit tumor growth and metastasis. The prepared ethylene diamine tetraacetic acid-magnesium (EDTA-Mg), on the one hand, chelates Ca2+ on the surface of tumor cells to form EDTA-Ca, causing the dissociation of tumor cells. Meanwhile, E-cadherin is downregulated, while vimentin and matrix metalloproteinase 2 (MMP-2) are upregulated, indicating the occurrence of EMT. On the other hand, after EDTA-Ca is endocytosed by tumor cells, it deprives Fe in the lysosomes to form EDTA-Fe, which induces ferroptosis through a Fenton reaction. Ferroptosis, combined with the initially released Mg2+, synergistically amplifies the immune response, thereby inhibiting tumor metastasis. To the best of our knowledge, such a strategy of artificially simulating EMT for tumor treatment has hitherto not been reported.