Precisely designed Fe _x ( x = 1–2) cluster nanocatalysts for effective nanocatalytic tumor therapy

Atomically dispersed metal clusters are considered as promising nanocatalysts due to their excellent physicochemical properties. Here, we report a novel strategy for precisely designing Fe_x (x = 1-2) cluster nanocatalysts (Fe₁-N-C and Fe₂-N-C) with dual catalytic activity, which can catalyze H₂O₂ into reactive oxygen species (ROS) and oxidize glutathione (GSH) into glutathione disulfide simultaneously. The adsorption energies of Fe-N sites in Fe₂-N-C for GSH and H₂O₂ intermediates were well controlled due to the orbital modulation of adjacent Fe sites, contributing to the higher dual catalytic activity compared to Fe₁-N-C. Additionally, tamoxifen (TAM) was loaded into Fe₂-N-C (Fe₂@TDF NEs) to down-regulate the intracellular pH for higher Fenton-like catalytic efficiency and ROS production. The generated ROS could induce apoptosis and lipid peroxidation, triggering ferroptosis. Meanwhile, upregulation of ROS and lipid peroxidation, along with GSH depletion and GPX4 downregulation could promote the apoptosis and ferroptosis of tumor cells. In addition, the lactic acid accumulation effect of TAM and the high photothermal conversion ability of Fe₂@TDF NEs could further enhance the catalytic activity to achieve synergistic antitumor effects. As a result, this work highlights the critical role of adjacent metal sites at the atomic-level and provides a rational guidance for the design and application of nanocatalytic antitumor systems.