Recombinant proteins can be very potent, but their therapeutic application can be strongly hampered by inappropriate distribution, dosage, kinetics or toxic effects. Targeted delivery of proteins such as cytokines would be strongly desirable.
DNA therapeutics comprise the delivery of genetic information on a piece of DNA as therapeutic prodrug. This prodrug can be transcribed and translated into a protein (the actual drug) within the target cells, preferably in a tissue-specific and bio-regulated fashion. Basically, two types of nonviral gene transfer systems  have been developed: particle-based systems, with DNA packaged into cationic lipids or polymers; and physical techniques which are based on combining DNA with a physical device. Intramuscular administration of naked DNA has already proven as interesting concept for vaccination , despite the low efficiency of the method. Two physical device technologies, electroporation and the gene gun, were found to enhance gene expression levels up to 1000- fold over injection of naked DNA alone. This enhancement has also recently been shown by several groups to trigger immune responses against defined antigens in several species .
We have generated particle-based systems that can target gene delivery and expression into distant target tissues. We use DNA polyplexes conjugated with cell-binding ligands such as transferrin for receptor-mediated endocytosis. The surface charge of complexes is masked by covalent coating with polyethylenglycol (PEG). Tumor targeting has been demonstrated in mouse models after systemic administration. With systemically applied tumor necrosis factor (TNF) alpha gene, tumor necrosis and regression of tumors was observed, but no systemic TNF-related side effects. Opportunities to apply local or systemic DNA therapeutics for inflammatory diseases will be discussed.