Although much effort has been extended to the efficient cancer therapies, the drug resistance is still a major obstacle in cancer chemotherapeutic treatments. Almost 90% of the cancer therapy failure is caused by the relative problems. Recently, the application of drug coated polymer nanospheres and nanoparticles to inhibit the related drug resistance has attracted much attention. In this report, we have explored a novel strategy to inhibit the multidrug resistance of the targeted tumor cells by combining the unique properties of tetraheptylammonium capped Fe₃O₄ magnetic nanoparticles with the drug accumulation of anticancer drug daunorubicin. Our results of confocal fluorescence and atomic force microscopy (AFM) as well as electrochemical studies demonstrate the remarkable synergistic effect of Fe₃O₄ nanoparticles on drug uptake of daunorubicin in leukemia K562 cells. These observations indicate that the interaction between the magnetic nanoparticles Fe₃O₄ and biologically active molecules on the membrane of leukemia cell lines may contribute to their beneficial effect on cellular uptake so that the synergistic enhanced effect of magnetic nanoparticles Fe₃O₄ on drug uptake of drug resistance leukemia K562 cells could be observed upon application of the Fe₃O₄ nanoparticles. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006