A Highly‐Active Chemodynamic Agent Based on In Situ Generated Copper Complexes from Copper Hexacyanoferrate Nanoparticles

Abstract Copper hexacyanoferrate (Cu ₂ Fe(CN) ₆ ) nanocubes with a homogeneous size under 100 nm are synthesized by self‐assembly from Cu ²⁺ and Fe(CN) ₆ ³⁻ precursors. Similar to previous reports with catalysts containing Cu and Fe, the objective is to produce a nanoparticle catalyst that can promote glutathione (GSH) oxidation thanks to the Cu contribution, plus some ROS production through Fenton‐like processes fostered by Fe. Unexpectedly, the catalytic activity for GSH oxidation are much higher (≈50%) than those obtained with equal Cu amounts provided as CuCl ₂ . Furthermore, in the presence of GSH concentrations characteristic of the tumor microenvironment, the nanocubes disassembled homogeneously, without a noticeably change of composition. These results suggest that this strong increase of catalytic activity arises from synergistic coordination of the released Cu ²⁺ and Fe(CN) ₆ ³⁻ ions that facilitate GSH deprotonation, accelerating its oxidation. Given the role of GSH in the nanoparticle disassembly process, a selective action of the catalyst can be obtained: lethal doses as low as 18 ppm of Cu are obtained for U251‐MG cancer cells while healthy fibroblasts are largely spared.