[Fe^IIICl(TMPPH₂)][Fe^IIICl₄]₂: A Stand-Alone Molecular Nanomedicine That Induces High Cytotoxicity by Ferroptosis

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [Fe^IIICl(TMPPH₂)][Fe^IIICl₄]₂ (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC₅₀) values in the range of 0.098-3.97 μM (0.066-2.68 μg mL^-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H₂O₂, converting H₂O₂ to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.