Ultrahigh density copper (Ⅰ) single atom enzymes for tumor self-cascade catalytic therapy

Cu (Ⅰ) single-atom enzymes (SAEs) have attracted considerable attention in tumor sequential catalysis therapy. However, their complex preparation process, lower atom loading capacity and uncontrollable valence state limit their clinical practices. Herein, we propose a convenient strategy for preparing Cu (Ⅰ) SAEs through the self-carbonization and reduction of organic solvents and CuⅡ salts. Formamide can easily be condensed into a linear macromolecular chain for chelating CuⅡ because of its high N content and vacant ligand sites. The resultant carbon nitride-based fragments reduce CuⅡ to CuⅠ. An unprecedented sequential catalytic performance for glutathione depletion and subsequent amplified hydroxyl radical generation is performed on the obtained C3N4 supported Cu (Ⅰ) SAEs (denoted as Cu-CN) with an ultrahigh density of 2.19 atoms/nm2 (23.36 wt%), in which the CuⅠ species serve as the active sites. The subversion of the homeostasis of the tumor microenvironment brought about by the Cu-CN produces efficient ferroptosis and apoptosis in cancer cells, resulting in a high tumor inhibition rate of 89.17 %. This study provides a novel strategy for fabricating valence controlled SAEs supported on C3N4 for catalytic applications.