We developed a simple and efficient method for fabricating a taste-masked oral drug delivery system (DDS) that regulates the release of unpleasant drug taste via the change in pH value in the physiological environment of the alimentary canal. In this drug delivery system, a pH-sensitive metal–organic coordination polymer (CP), Fe-4,4′-bipyridine (Fe-bipy) complex, works as a taste-masker. The pH-sensitive Fe-bipy was grafted onto the mesoporous silica nanoparticles (MSNs) containing the model bitter drug mequindox (MEQ) in its mesopores through metal–organic coordination cross-linking, resulting in the CP-coated nanodrug MSN-NH₂-MEQ@Fe-bipy. In artificial saliva (pH 6.6), Fe-4,4′-bipyridine CPs effectively prevent the leaking of the loaded guest molecule MEQ. On the other hand, in artificial gastric fluid (pH 1.0), the coordination bonds of the Fe-4,4′-bipyridine complex were broken, leading to the release of MEQ molecules from MSN-NH₂-MEQ@Fe-bipy. The results indicate that the simple and efficient preparation method for taste-masked MSN-NH₂-MEQ@Fe-bipy could provide new insights into taste-masking technology by using pH-responsive smart nanomaterials.