Gene therapy using biocompatible cationic liposomes is amongst promising approaches that decreases death from cancers. Here an invasive multidrug resistant cell model has been developed by lentiviral transfection. In parallel phospholipids have been covalently conjugated to TAT, MMP2, and Herceptin. The functional lipids have been mixed to generate intelligent liposome harboring small interfering RNA (siRNA) with high efficiency. The final liposomal complex was uniformly monodisperse and particle dimension and zeta-potential were respectively around 200 nm and -42.21 mV. Minimal cytotoxic effects have been reported for nanocarriers due to good biocompatibility of the selected phospholipids. Flourescence-activated cell sorter (FACS) analyses have been represented that surface trastuzumab and TAT specifically promote cellular uptake of liposomes in the malignant tumor cells. Assessment of MDR1 transcript and protein expression has been exhibited maximum significant downregulation around of 128-fold and 50-fold, respectively after 48 hr of liposome exposure. As it has been concluded, targeted liposomes may become a potential tool in gene delivery for improving chemotherapeutic efficiency in cancer treatment.