Nanomaterials for effective drug delivery require zero pre-release and on-demand release of therapeutic drugs. In this work we demonstrate a novel drug delivery system composed of a mesoporous silica platform conjugated to CuS nanoparticles with two complementary DNA sequences. CuS nanoparticles act as both gatekeepers preventing pre-release of drugs and photothermal agents for effective killing of cancer cells. This system exhibits temperature and NIR-responsive DOX release, with an additional accelerated release rate with GSH treatment. Therefore, it can act as an effective anticancer drug delivery carrier with triggered drug release and efficient anti-cancer effect in vitro after NIR irradiation.