Following the initial findings over a decade ago that cationic lipids and polymers are able to carry genes into eukaryotic cells, much effort has been dedicated to improving transfec-tion efficiency via structural modifications of the carrier. Exploiting structure-activity relations led to molecules capable of transfecting adherent cell lines in culture at a multiplicity of infection of ca. 106 gene copies per cell. In vivo gene delivery, the prerequisite to gene therapy, is still orders of magnitude less effective.

Figure 10 Nuclear pore crossing of a hybrid DNA-NLS peptide conjugate. See the color insert for a color version of this figure.

It does not seem reasonable anymore to search for ''the'' molecule able to carry DNA across the numerous barriers. Vectors of the future will be composed, much like viruses, of multifunctional supramolecular systems that self-assemble around DNA. Programmed intracellular disassembly may well be part of a successful story, too, especially for coated or reticulated particles. Each component of the vector is devoted to a particular function. As illustrated above, some functions, such as integrin-mediated cell entry or NLS-directed entry into the nucleus, mime viruses. Some other solutions, such as monomolecular genome condensation via detergent dimeriza-tion, or endosome release by the proton sponge effect, have obviously not been exploited by the natural cell invaders. The consequences of increased complexity of the vectors on their development as gene medicines (88) are difficult to evaluate at this stage. In any case, the puzzle still has to be assembled prior to ressemblance to an artificial virus (89): this is yet another story.

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