Cyclic peptide gatekeepers with a capability of on–off drug release triggered by stimuli-responsive conformational transformation on the surface of mesoporous silica nanocontainers (MSNs) has several advantages such as facile introduction of targeting ligand, high targeting selectivity, and low enzymatic degradation. In this report, a dual functional cyclic peptide gatekeeper containing A6 sequence on the surface of MSNs is prepared for active targeting of cancer cells with high CD44 expression along with the capability of triggered drug release. The entrapped DOX is released from the MSNs with A6-containing cyclic peptide gatekeepers via conformational transformation of the peptide triggered by intracellular glutathione of the cancer cells. Furthermore, the MSNs effectively induce apoptosis in MDA-MB-231 cells (with CD44 expression) while not in SK-BR-3 cells (without CD44 expression).