pH-responsive systems are promising in their applicability to many areas, e.g., in drug delivery. Herein, we report a novel versatile pH−responsive system based on the coordination bonding of metal ions and functional groups in mesopores. Organic group functionalized mesoporous silica nanoparticles were employed as typical carriers for hosting metal ion binders and guest molecules to form a “host−metal−guest” architecture. The cleavage of either the “host−metal” or the “metal−guest” coordination bond, in response to pH variations, gives rise to a significant release of guest molecules under designated pH conditions. Using amino group functionalized mesoporous silica and choosing proper metal ions, the successful release of anticancer drugs bearing coordination binding groups was achieved at pH 5.0−6.5. Furthermore, a vector bearing pH-responsive binding functional groups is designed to assist in the release of drugs without significant binding capabilities. This route opens up a facile but powerful avenue for the design of various pH-responsive systems and new opportunities for their application in drug delivery.