Gene silencing has immense potential in the treatment of cancer. However, enhancement of its efficiency requires the development of specifically targeted and safe carrier systems. Cationic carriers are generally limited by their immunogenicity. Hence, in this study, we report hybrid liposomes encapsulating Poly (L-lysine)-siRNA complex to silence epithelial cell adhesion molecule (EpCAM), highly expressed in epithelial cancers. The hybrid liposomes LL1 (Egg PC:DSPE-PEG, 10:0) and hybrid immunoliposomes LL2 (Egg PC:DSPE-PEG, 8:2) linked with EpCAM antibody as the targeting ligand showed an encapsulation efficiency of 70% and 86%, respectively. LL2 liposomes with a zeta potential of −26 mV exhibited good colloidal stability in phosphate buffered saline containing bovine serum albumin and fetal bovine serum at 37 °C. Cell uptake studies showed increased uptake of the LL2 when compared to LL1 liposomes. Finally, the hybrid immunoliposomes were evaluated for their efficacy in regressing the tumor volume in SCID mice. Eight doses each of 0.15 mg/kg, which is among the lowest reported siRNA concentrations, were administered to the animals. About 45% reduction in tumor volume was achieved after 28 days in the mice treated with LL2 when compared with the positive control and LL1 treated groups. Thus, our results demonstrate that the ‘nano–in–nano’ concept of encapsulating poly (l–Lysine) complexed EpCAM siRNA in immunoliposomes may be a promising strategy to treat EpCAM-positive epithelial cancers, especially as an adjuvant therapy.