Multidrug resistance is the main reason for the failure of chemotherapy during the treatment of the tumor. To overcome multidrug resistance, this study attempts to develop a novel transdermal drug-delivery system (TDDS) loading cytotoxic drug and chemosensitizer. The polyethylenimine-modified ethosomes (Eth) and sodium cholate-modified ethosomes (Eth) were firstly fabricated, and then a novel TDDS based on the carriers complex of Eth/Eth was prepared by electrostatic interaction and evaluated both and . The Eth/Eth showed the excellent antitumor effect on treating melanoma, using doxorubicin and curcumin as the cytotoxic drug and chemosensitizer, respectively. The as-prepared TDDS composed of Eth/Eth loading multidrug is an effective means for treating melanoma.