Axial O Atom-Modulated Fe(III)-N₄ Sites for Enhanced Cascade Catalytic ¹O₂-Induced Tumor Therapy

The rational construction of efficient hypoxia-tolerant nanocatalysts capable of generating singlet oxygen (¹O₂) without external stimuli is of great importance for tumor therapy. Herein, uniformly dispersed and favorable biosafety profile graphitic carbon nitride quantum dots immobilized with Fe-N₄ moieties modulated by axial O atom (denoted as O-Fe-N₄) are developed for converting H₂O₂ into ¹O₂ via Russell reaction, without introducing external energy. Notably, O-Fe-N₄ performs two interconnected catalytic properties: glutathione oxidase-mimic activity to provide substrate for subsequent ¹O₂ generation, avoiding the blunting anticancer efficacy by glutathione. The O-Fe-N₄ catalyst demonstrates a specific activity of 79.58 U mg^-1 at pH 6.2, outperforming the most reported Fe-N₄ catalysts. Density functional theory calculations demonstrate that the axial O atom can effectively modulate the relative position and electron affinity between Fe and N, lowering the activation energy, strengthening the selectivity, and thus facilitating the Russell-type reaction. The gratifying enzymatic activity stemming from the well-defined Fe-N/O structure can inhibit tumor proliferation by efficiently downregulating glutathione peroxidase 4 activity and inducing lipid peroxidation. Altogether, the O-Fe-N₄ catalyst not only represents an efficient platform for self-cascaded catalysis to address the limitations of ¹O₂-involved cancer treatment but also provides a paradigm to enhance the performance of the Fe-N₄ catalyst.