Nanozymes have attracted widespread attention, and rationally designing high-activity nanozymes to improve their application performance are a long-term objective. Herein, taking metal-organic frameworks-derived Co3O4 polyhedron with large surface area and high porosity as nanoconfinement carriers, Co3O4@MnO2@CDs polyhedron was successfully synthesized by the room-temperature reduction of MnO4− ions and physical load of carbon dots (CDs). Through cancer cells-triggered double antibody sandwich strategy, the Co3O4@MnO2@CDs polyhedron were introduced to the TiO2 nanoparticle (NPs) modified electrode, leading to the decreased photocurrent. The Co3O4@MnO2@CDs polyhedron can not only quench the photocurrent of TiO2 NPs, also act as nanozymes to catalyze precipitates. Moreover, the precipitates can not only reduce the photoelectrochemical (PEC) response, also increase the quenching capacity of the Co3O4@MnO2@CDs polyhedron. Additionally, the steric hindrance effect of the Co3O4@MnO2@CDs-Ab conjugates further weaken the photocurrent. Based on the multifunctional Co3O4@MnO2@CDs polyhedron, the proposed PEC biosensor for the detection of A549 cancer cells exhibits a wide linear range from 102 to 106 cells/mL and a low detection limit of 11 cells/mL. Furthermore, this strategy can differentiate between lung cancer patients and healthy individuals. The designed multifunctional Co3O4@MnO2@CDs nanozymes provide a new horizon for PEC detection of cancer cells, and may have great potential in early clinical diagnosis and biomedical research.