We have developed a targeted DNA delivery system for the treatment of lung cancer by gene therapy. This system uses epidermal growth factor (EGF), which has receptors that are overexpressed on lung cancer cells, and couples receptor-mediated endocytosis with an endosomal lysis agent for targeted gene delivery. Recombinant human EGF was chemically modified to allow for its attachment to DNA through the use of the poly-cation poly-L-lysine (PLL). The EGF/PLL conjugate was able to bind DNA and when incubated with several different lung cancer cell lines, high levels of gene expression resulted when uptake was performed in the presence of replication-defective adenovirus, which was used only as an endosomal lysis agent. When the adenovirus was coupled directly to the EGF/DNA complex, the levels of gene expression were up to fourfold higher. Depending on the lung cancer cell line and the type of complex used, approximately 14% to 99% of the cells showed DNA uptake, whereas a colon adenocarcinoma cell line that does not express the EGF receptor at the cell surface showed little or no DNA uptake. As a result, the EGF/DNA complex can deliver therapeutic genes to lung cancer cells by targeting to specific receptors.