BACKGROUND: Ulcerative colitis (UC) is a chronic and recurrent digestive tract disease that can lead to significant morbidity and mortality. The pathogenesis of UC is intricately associated with the presence of reactive oxygen species (ROS). Prussian blue (PB), an inorganic nanozyme with potent antioxidant properties, has been extensively applied in the treatment of various inflammatory conditions and tumors. However, despite the explicit antioxidant properties, the underlying molecular mechanism of PB nanozyme in the treatment of UC remains poorly understood. Furthermore, there is a deficiency in antioxidants that possess specific targeting capabilities towards UC lesions. The present study pioneered the fabrication of neutrophil (N)-macrophage (M) hybrid membrane-coated PB (NM-PB) nanozyme for the treatment of UC and investigated its underlying molecular mechanism. RESULTS: We have successfully constructed PB, N-PB, M-PB, and NM-PB nanozymes. In both the colitis cell model and UC mouse model, compared with PB, N-PB, and M-PB nanozymes, NM-PB nanozymes exhibited remarkable targeting capabilities, significantly enhancing the localization and uptake of PB nanozymes at the lesion site. NM-PB nanozymes significantly reduced levels of ROS (•OH, •OOH, and H CONCLUSION: The NM-PB nanozymes provide a promising and innovative alternative for the treatment of UC, offering enhanced targeting and efficacy through their unique design and mechanism of action.