Polypeptide-Folded Artificial Ferroprotein Promotes Ferroptosis in Multiple Tumor Cells

Although the current nanozymes, such as Fe₃O₄ nanoparticles, exhibit biocatalytic activities, they dramatically differ from natural enzymes, lacking a degradable organic framework and an intrinsically flexible structure. Single-chain folding of a synthetic polypeptide by metal coordination can mimic metalloproteins more similarly. A triblock PEG-polypeptide copolymer, poly(ethylene glycol)-<i>b</i>-poly(but-3-yn-1-yl glutamate)-<i>b</i>-poly(<i>tert</i>-butyl glutamate) [EG₁₁₃<i>-b-</i>(Glu-yne)₄₈<i>-b-</i>(Glu-tBu)₆₁], was synthesized by NCA polymerization. The alkyne side groups on the central Glu-yne block were intramolecularly cross-linked by Fe₃(CO)₁₂ coordination. After thermolysis, the CO ligand was completely removed, yielding an artificial ferroprotein (AFP) with amorphous Fe/FeO<i>_x</i> nanoclusters locked within the cross-linked region. While the parent triblock copolypeptide displayed negligible cytotoxicity on human normal cell lines (BEAS-2B and LO2), AFPs induced evident ferroptosis on four different cancer cell lines (PANC-1, HT1080, MCF-7, and A549) even with a low Fe content at 1.6 wt %.