Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable.Combination therapy is a commonly used method for overcoming MDR.In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA),a derivative of artemisinin,in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells.We developed a tumor-targeting codelivery system,in which the two drugs were co-encapsulated into the mannosylated liposomes (Manliposomes).The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of-15.8 mV.In the HCT8/ADR cells that overexpress the mannose receptors,the Man-liposomes altered the intraceliular distribution of Dox,resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 μg/mL) among all the groups.In a subcutaneous HCT8/ADR tumor xenograft model,administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59％,compared to that of 47.46％ or 70.54％,respectively,for the treatment with free Dox or free Dox+DHA.The mechanisms underlying the anti-MDR effect of the Manliposomes involved preferential nuclear accumulation of the therapeutic agents,enhanced cancer cell apoptosis,downregulation of Bcl-xl,and the induction of autophagy.