Cyclodextrins tethered onto a mesoporous silica nanoparticle via disulfide stalking are effective gatekeepers not only to entrap guest molecules in the pore but also to release the guest in response to glutathione (GSH). The PEGylated nanocontainers also exhibit efficient GSH-mediated release of doxorubicin in cancer cells. Our approach offers unique applications for multifunctional delivery systems.