Metal-organic frameworks (MOFs)-based peroxidase mimics have been seldom applied in the biomedical field, especially in vivo. One of the main reasons is their optimum reactions occur in strong acidic environments with a pH of 3-4, severely limiting their applications in living systems where neutral pH is usually required. Other types of peroxidase mimics also suffer such a fatal defect. Additionally, the direct introduction of the relatively high concentrated and toxic reaction reagent HO would induce undesired damage to normal tissues. Herein, a MOF-based hybrid nanocatalyst as a benign and self-activated cascade reagent has been constructed. Owing to better catalytic performance compared with three-dimensional bulk MOF, an ultrathin two-dimensional (2D) MOF (2D Cu-TCPP(Fe)) nanosheet is chosen as a model of peroxidase mimic to physically adsorb glucose oxidase (GOx) for fabricating such a hybrid nanocatalyst. Nontoxic glucose can be continuously converted into abundant gluconic acid and HO by GOx, avoiding the direct use of relatively high concentrated and toxic HO and minimizing the harmful side effects. The generated gluconic acid can decrease the pH value from 7 to 3-4, dramatically activating the peroxidase-like activity of 2D Cu-TCPP(Fe) nanosheets. Meanwhile, the produced HO is used for subsequent catalysis of activated 2D Cu-TCPP(Fe) nanosheets, leading to efficient generation of an extremely toxic hydroxyl radial and antibacterial capacity. In vitro and in vivo results illustrate the designed benign and self-activated cascade reagent possesses a robust antibacterial effect with negligible biotoxicity.