We have contributed to the development of the first generation cationic liposome. One such formulation, DC-chol/DOPE liposome, was the first to be tested in human clinical trials in 1992. Like many other similar cationic lipid formulations, DC-chol/DOPE liposome does not condense DNA strongly and tends to aggregate with DNA at high concentrations. Although the formulation is effective for local and regional administration, systemic administration with this type of liposome has proven to be difficult. Further improvement by adding a DNA condensation reagent, such as protamine, has resulted in small (<100 nm) and highly condensed nanoparticles which we named LPD formulation. LPD has a unique structure as revealed by cryo EM. It contains a condensed core, which is surrounded by two lipidic membranes, similar to an enveloped virus. Intravenous administration of LPD causes systemic gene expression, primarily in the lung and spleen. Interestingly, metastatic tumor cells in the lung are also transfected. Using several anticancer genes, including RB and p53, we have demonstrated anticancer activities of the LPD formulation. However, the activity is further augmented by the immune-stimulating CpG motifs in the plasmid DNA, which causes rapid induction of TNF-alpha, gamma-IFN, and other pro-inflammatory cytokines. Such an immune response has significantly contributed to the final anticancer activity by inducing a specific CTL response in the host. Several preclinical gene therapy studies will be discussed.