© 2022 Elsevier B.V.Combinational gene and chemo-therapy approach has been investigated for more effective treatment of cancer. In this report, we demonstrated a multifunctional carrier system based on gold nanoparticles (AuNPs) for co-delivery of siRNAs against Bcl-2, an anti-apoptotic gene, and doxorubicin (Dox), a well-known chemotherapy drug, to obtain enhanced treatment efficacy against advanced breast cancer. Bcl-2-siRNAs were attached to the surface of 13 nm AuNPs, and Dox was directly intercalated to the siRNA molecules without any need for complex chemical modifications or coating. Successful loading of both siRNA and Dox therapeutics to AuNPs and formation of multipurpose carrier system were demonstrated. Dox-loaded carrier system exhibited cytotoxic effect on triple-negative breast cancer (TNBC) cells and provided efficient drug internalization. Moreover, enhanced apoptosis and inhibition of cancer cell proliferation were achieved with dual delivery of Bcl-2 siRNA and Dox by the co-delivery AuNPs system. In addition, silencing of the Bcl-2 gene along with chemotherapy provided reduced colony formation and cell migration of breast cancer cells. In conclusion, inhibition of Bcl-2 expression increased the therapeutic activity of Dox on TNBC. Nevertheless, our nano-carrier system has also been tested against MCF7 cell line. Our results demonstrated that the prepared multifunctional delivery system presented an effective vehicle for simultaneous delivery of gene therapy and chemotherapy agents.