Preclinical studies showed that TRAIL therapy is safe and effective to combat cancers, but clinical outcomes have been less than optimal due to short half-life of TRAIL protein, insufficient induction of apoptosis and TRAIL resistance displayed in many tumors. In this study, we explored co-delivery of a TRAIL expressing plasmid (pTRAIL) and complementary siRNAs (silencing BCL2L12 and SOD1) to improve the response of breast cancer cells against TRAIL therapy. It is desirable to co-deliver the pDNA along with siRNA using a single delivery agent, but this is challenging given different structures of long/flexible pDNA and short/rigid siRNA. Towards this goal, we identified an aliphatic lipid-grafted low molecular weight polyethyleneimine (PEI) that accommodated both pDNA and siRNA in a single complex. Co-delivery of pTRAIL with BCL2L12 or SOD1 specific siRNAs resulted more significant cell death in different breast cancer cells as compared to separate delivery without affecting non-malignant cells viability. Ternary complexes of lipopolymer with pTRAIL and BCL2L12 siRNA significantly retarded the growth of breast cancer xenografts in mice. The enhanced anticancer activity was attributed to increased in situ secretion of TRAIL and sensitization of breast cancer cells against TRAIL by the co-delivered siRNAs. The lipid-grafted PEIs capable of co-delivering multiple types of nucleic acids can serve as powerful carriers for more-effective complementary therapeutics.