Cancer is a leading cause of death. Mesoporous nanomaterials with stimuli sensitivity have received increasing interest as efficient anti-cancer drug carriers. Here, we report hybrid mesoporous nanoparticles of PEGylated silica-poly[2-(dimethylamino)ethyl acrylate] (PEGylated MSN-g-PDMAEA) that can deliver and release the anti-cancer drug doxorubicin (DOX) to tumor cells in a pH dependent switch on/off status. The reversible pH sensitivity resulted in nanoparticles with enhanced functionality through controllable release of the anticancer drug. Confocal laser scanning microscopy (CLSM) and three dimensional (3D) image capture of the intracellular localization of nanoparticles revealed the fast and efficient drug delivery in the human hepatocellular carcinoma cell line. The results highlight the potential of these pH sensitive silica nanoparticles as a novel system for the delivery and controlled release of hydrophobic anti-cancer drugs in the treatment of solid tumors.