Nanodiamond as a carrier for transporting chemotherapy drugs has emerged as a promising strategy for treating cancer. However, several factors limited its extensive applications in biology, such as low drug loading, easily cluster and a high drug loss under physiological environment. In this work, to ensure high drug capacity and low drug leakage in physiological conditions, and especially ensure to be delivered to tumor region, a smart pH-responsive drug delivery system was designed and prepared by DOX adsorbed onto PEGylated nanodiamond in sodium citrate medium (ND-PEG-DOX/Na3Cit, NPDC). The system can significantly enhance cellular uptake to exert therapeutic effect in comparison to free drug. And more importantly, DOX was released in a sustained and pH-dependent manner and exhibits excellent stability under neutral conditions. In addition, NPDC could enter into cells via both clathrin and caveolae-mediated endocytosis pathway, and then dissociated DOX migrated into nucleus to block the growth of cancer cells. Furthermore, NPDC can significantly inhibit the cell migration and change the cell cycle. Excitingly, the NPDC system was very smart to enrich at the tumor site in vivo effectively and to enhance antitumor efficiency with low toxicity beyond conventional DOX treatment in cancer cells and nude mouse model. So this study introduces a simple and effective strategy to design a promising drug delivery platform for improving the biomedical applications of the smart nanodiamonds carriers. amount of loaded DOX is relative poor and the drug dissociation in physiological environment is slightly high. Scheme 1 Schematic illustration of the fabrication of an intracellular pHresponsive NPDC delivery system for cancer therapy.