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Multidrug resistance (MDR) is one of the major obstacles for successful treatment of breast cancer.Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) and anti-apoptotic proteins like survivin are the major reasons responsible for MDR.Herein, a gambogic acid (GA)-loaded mixed micelle system made of poly(lactic-co-glycolic acid)-b-poly(L-histidine)-b-poly(ethylene glycol) (PLGA-pHis-PEG) and D-α-tocopheryl polyethylene glycol 1000 (TPGS) was developed for overcoming MDR by the integrated effects of the pH-sensitive behavior of PLGA-pHis-PEG, P-gp inhibiting activity of TPGS and survivin downregulation ability of GA.