The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. In this study, we prepared a new capped mesoporous silica nanoparticle as a potential material for colon-specific drug delivery. This material consisted of nanoscopic mesoporous MCM-41 supports loaded with ibuprofen and capped with a bridged silsesquioxane with azo groups. X-ray diffraction, N2 sorption analysis, transmission electron microscopy, UV–vis diffusion reflectance spectroscopy, and 29Si magic angle spinning nuclear magnetic resonance were used to verify the well-ordered mesostructure and the successful grafting of bridged silsesquioxane on the surface of the mesoporous material. The material showed “zero release” in simulated gastric fluid and simulated intestinal fluid. The opening and release of cargo occurred in simulated colonic fluid with azo-reductase due to the reductive cleavage of the azo bonds. However, no release of ibuprofen was observed in phosphate-buffered saline without enzyme. These results indicated that the capped mesoporous material showed excellent behavior for colon specificity and could be a potential material for colon-specific drug delivery.