On the basis of amino group-functionalized mesoporous materials, a pH-responsive system by constructing a designable coordination bonding-based "NH-metal-DOX" architecture in mesopores has been investigated. The DOX can be released by the cleavage of either the "NH-metal" or the "metal-DOX" coordinate bonding in response to pH variations. Here, the strengths of coordination bondings on both sides have been designed and fabricated from the aspects of NH loading amount, metal ion, and the counteranion accompanying the metal ion. It has been found that (i) the increase of amino group loading led to increased release percentage of the DOX under physiological condition due to a small number of "metal-DOX" bondings resulted from too many "NH -metal" bondings, and this tendency finally resulted in a decrease in its stability; (ii) the pH-sensitivity can be controlled by choosing the type of metal ion; and (iii) the physiological stabilities of "NH -metal-DOX" architectures formed by various metal sources are in the decreasing order of CHCOO > NO > SO > Cl, indicating that different counteranions gave rise to different coordination bonding strengths of the architectures. Amino group loading amount of 2.4 mmol/g and CHCOO counterion were suitable for "NH -Zn-DOX" pH-responsive delivery system, which was stable under physiological condition, while it was unstable with the DOX release triggered by the slight decrease to pH 6.0-5.0. The efficient cellular uptake of this pH-responsive system for cancer cells has been confirmed by cell assay. This coordination bonding-based pH-responsive system provides a new insight into the molecular factors governing the strength of chemical bonds in restrictive domain, which would open up new possibilities of porous materials for advanced applications in adsorption and desorption of biological and paramedical materials for antitumor therapy. © 2011 American Chemical Society.