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 Cu-II species into Cu-I 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.