In this work, a nano-mimetic enzyme Co3O4 nanoparticles with catalytic effect on the reduction of H2O2, was synthesized and used to label C-reactive protein antibody. Au nanoparticles (Au NPs) were loaded on COF-TpPa-1 to form Au NPs@COF-TpPa-1 with good biocompatibility and adsorption ability. A sandwich C-reactive protein immunosensor was prepared using Au NPs @COF-TpPa-1 as the immobilization matrix. The catalytic current of Co3O4 nanoparticles to the reduction of H2O2 was measured by the chronoamperometry which is in proportion to the concentration of CRP. The linear range of this immunosensor was 0.05-80 ng/mL with the linear correlation coefficient of 0.9955. The method demonstrated a good sensitivity with a detection limit of 0.017 ng/mL (S/N = 3) for CRP. When the C-reactive protein immunosensor was applied to real serum samples analysis, the satisfied results were obtained, indicating that the immunosensor is of prospect of application.