Over expression of drug efflux transporters such as P-glycoprotein (P-gp) cumulatively leading to multidrug resistance (MDR) embodies a major hindrance for successful cancer therapy. A paradigm nanomedicinal approach involving an anticancer drug and modulators of drug resistance within one multifunctional nanocarrier-based delivery system represent an ideal modality for the treatment of MDR. In this regards, we have developed a cationic polymeric nanoparticulate system loaded with MDR1-siRNA and doxorubicin. Results indicated augmented synergistic effect of combinational nano-formulation in overcoming MDR in MCF-7/ ADR cells. Therefore, the above regime could be a promising co-delivery system for effective therapy of drug resistant breast cancer. (C) 2014 Elsevier B.V. All rights reserved.