Self‐assembled single‐site nanozyme for tumor‐specific amplified cascade enzymatic therapy

Nanomaterials with enzyme‐mimicking activity (nanozymes) show potential for therapeutic interventions. However, it remains a formidable challenge to selectively kill tumor cells through enzymatic reactions, while leaving normal cells unharmed. Herein, we present a new strategy based on a single‐site cascade enzymatic reaction for tumor‐specific therapy that avoids off‐target toxicity to normal tissues. A copper hexacyanoferrate (Cu‐HCF) nanozyme with active single‐site copper exhibited cascade enzymatic activity within the tumor microenvironment: Tumor‐specific glutathione oxidase activity by the Cu‐HCF single‐site nanozymes (SSNEs) led to the depletion of intracellular glutathione and the conversion of single‐site CuII species into CuI for subsequent amplified peroxidase activity through a Fenton‐type Harber–Weiss reaction. In this way, abundant highly toxic hydroxyl radicals were generated for tumor cell apoptosis. The results show that SSNEs could amplify the tumor‐killing efficacy of reactive oxygen species and suppress tumor growth in vivo.Ministry of Education (MOE)National Research Foundation (NRF)Accepted versionThis research is supported by the National Key Research and Development Program of China (Stem Cell and Translational Research, 2016YFA0101202), the Singapore Academic Research Fund (RT12/19), the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-03), and the National Natural Science Foundation of China (21571168)