Similar to the majority of biological molecules, DNA is degraded rapidly in the body. Its encapsulation into a delivery system increases circulation time and permits accumulation of the drug in certain organs. Lipid-based soft nanoparticles have the ability to encapsulate or complex DNA and shuttle it into the cells by overcoming cellular and molecular barriers. The use of state-of-the-art technology for the systematic evaluation of the gene transfer efficiency of the novel nanoparticles leads to the development of in vivo gene delivery systems for topical non-invasive administration. These delivery systems find application in the development of new gene therapy for dermatology, immunology/vaccines and neurodegenerative diseases.