Targeted delivery of polymer-based nanoparticles has been considered as an efficient approach to transfer genetic materials such as plasmid DNA and siRNA. Given the presence of the binding site for tetraiodothyroacetic acid on integrin receptor and overexpression of integrin ?V?3 receptor on tumor cells, early escape from endosomal compartment by the proton sponge effect of PEI and entry of tetraiodothyroacetic acid conjugated nanoparticles into cell nucleus by TR receptors, we hypothesized that conjugation of tetraiodothyroacetic acid with PEI may overcome three major barriers considered as the main obstacles in polycation-based gene delivery. In order to test the hypothesis, modified polymer/plasmid DNA complexes were prepared and their ability in transferring plasmid encoding Interleukin-12 was investigated. Moreover, the conjugates were characterized with respect to plasmid DNA condensation ability, particle size and zeta potential as well as cell-induced toxicity and plasmid protection against DNase degradation. The results demonstrated that tetraiodothyroacetic acid derivatives of PEI were able to condense plasmid encoding IL-12 gene at a carrier to plasmid DNA (C/P) weight ratio ? 2:1. The measured particle size was around 180 nm. The highest level of IL-12 gene expression was achieved by the nanoparticles prepared by modified PEI at carrier to plasmid ratio of 8 where they could increase the level of gene expression up to 4 times compared to that of naked plasmid. The cell viability in such C/P ratios is up to 85%. These results suggest that tetraiodothyroacetic acid conjugation of PEI is a simple modification strategy for future investigations aimed at developing a targeting gene vehicle.