Rapid release and clearance of antitumor drugs in vivo are the main factors used to evade the effectiveness of chemotherapeutics. Targeted delivery and controlled release of drugs are the most pressing dilemmas in cancer therapy. Herein we report the design and fabrication of multifunctional mesoporous silica nanoparticles coated with poly(N-isopropylacrylamide)-co-acrylic acid and calcium phosphate (MSCNs) with pH-triggered chemotherapeutic release and dual-targeting functions. By decorating the nanoparticle surface with a transferrin (Tf)/RGD ligand, these nanoparticles are capable of not only recognizing the intrinsic pH difference between tumor and normal tissues, but also targeting the lesion location. It was shown that Tf/RGD-MSCNs delivered the anti-tumor drug doxorubicin more efficiently into lysosomes and the resulting DOX-loaded nanoparticles (DOX-Tf/RGD-MSCNs) showed a stronger inhibitory effect towards tumor cell growth than free DOX and DOX delivered by unmodified MSNs. Moreover, the nanoparticles are more biocompatible than uncoated mesoporous silica nanoparticles. All these results indicate that Tf/RGD-MSCNs have great potential as a novel drug carrier in therapeutic applications against cancers.