Receptor-mediated gene delivery with non-viral DNA carriers

To achieve effective nucleic acid-based therapy, natural carriers, i.e. vir uses, as well as synthetic carriers have been developed. The majority of th e non-viral systems are based on DNA compaction into small particles by cat ionic compounds, which are most often polymers and lipids. Optimal in vitro gene delivery with the cationic carriers requires an excess of positive ch arges with respect to DNA phosphates. However, the overall positive charge of these particles limits their application in vivo because: i) the half-li fe of positively charged DNA complexes, injected intravenously, is very sho rt, and ii) it does not allow-site-specific delivery of the gene of interes t. To overcome this problem, the most attractive strategy consists in repla cing the non-specific electrostatic interactions between cells and the tran sfection complexes with a cell-specific interaction that triggers a recepto r-mediated endocytosis of the targeted DNA complexes. Such an active target ing requires the identification of receptors present at the surface of the target cells and the use of ligands which binds with a high specificity and affinity to such recognition sites. In this review, we will focus on three examples of receptors that have been used for the targeting of DNA complex es: the Gal/GalNAc receptor followed by the integrin- and folate receptors. Some important principles underlying targeted transfection will also be ev oked such as the importance of the conjugation chemistry, the nature of the ligand-receptor interactions, the occurrence of limited windows of the com plex charge where targeting is observed.