Currently, multidrug resistance (MDR) is the major challenge of nanotechnology in cancer treatment. In this study, a series of amphiphilic poly(styrene-co-maleic anhydride)-graft-poly(2-(N,N-dimethylamino)ethyl methacrylate) graft copolymer [PSMA 89 -g-P(DMA 16 -co-SD)] micelles were prepared. PSMA 89 -g-P(DMA 16 -co-SD) graft copolymers were first synthesized by grafting different amounts of sulfadimethoxine (SD) onto PSMA 89 -g-P(DMA 16 -co-SD). The PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles exhibited a thermo and pH dual-controlled charge reversal properties without cleavage of chemical bonds. The surface charge of PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles reversed from positive to negative after the solution temperature increased from 25 1C to 37 1C at pH 7.4. However, when the pH value was adjusted to 6.8 at 37 1C, the surface charge became positive again. The thermo and pH dual-controlled charge reversal not only resulted in a controlled doxorubicin (DOX) release but also effectively enhanced the cellular uptake of DOX-loaded PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles through electrostatic absorptive endocytosis. MTT assay demonstrated that DOX-loaded PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles showed the highest inhibition growth of DOX-resistant ovarian carcinoma (A2780/Dox R ) cells with pH 6.8 at 37 1C among those with pH 7.4 at 37 1C and pH 7.4 at 25 1C, leading to higher efficiency in overcoming MDR of A2780/Dox R cells. Therefore, PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles can be used as intelligent drug-delivery systems to overcome MDR of cancer cells. † Electronic supplementary information (ESI) available: Synthesis of hydroxylpoly(N,N-dimethylaminoethyl methacrylate) (HO-PDMA), Dz, LCST and zeta potential change of DOX loaded PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles. See Scheme 1 Possible mechanism of charge reversal and the cell uptake mechanism for PSMA 89 -g-P(DMA 16 -co-SD 56 )/DOX micelles. (a) DOX-loaded PSMA 89 -g-P(DMA 16 -co-SD 56 ) micelles with positive charge at 25 1C and pH 7.4; (a and b) the micelles were negatively charged in blood circulation; (b and c) the negative surface charge of the micelles was reversed to positive after the micelles reached the tumors; (c and d) uptake efficiency was enhanced; and (d-f) DOX molecules were released from the micelles in the cells to overcome drug resistance.