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The copper(II) diethyldithiocarbamate (Cu(DDC)2) complex exhibited excellent inhibition to cancer cells.The usual administration is intravenous injection for disulfram and oral for copper. A new strategy was reported to improve the administration efficiency of the Cu(DDC)2 drug. Poly(lactide-co-glycolide)(PLGA) nanoparticles were used to trap disulfram and copper gluconate separately, the two types of drug loaded nanoparticles were injected in mesothelioma-bearing nude mice via intraperitoneal injection.The in vivo formation of Cu(DDC)2 complex was induced by disulfiram and Cu2+ released from PLGA nanoparticles. This strategy avoided many obstacles in the use of Cu(DDC)2 complex as chemotherapeutic and exhibited excellent anticancer activity to mesothelioma.