A chemical solution to this dilemma was found, based on in situ chemical conversion of the cationic detergent into a cationic lipid (Fig. 2) [3]. This two-step process leading to monomolecular and stable DNA particles was validated using cysteine based cationic detergents as condensing agents, and thiol air oxidation into disulfide as the conversion reaction [4]. As shown in Fig. 2, the particles are monodisperse and their size (25 nm) corresponds to the volume of a single molecule of plasmid DNA. Moreover, such particles are capable of migrating through an agarose gel in electrophoresis conditions, in contrast to normal cationic lipid /DNA complexes. Surprisingly, the particles moved even faster than plasmid DNA itself, showing that Stokes diffusion of the compacted DNA particle is easier than De Gennes reptation of the corresponding extended DNA polymer [5]. Improved in vivo diffusion within tissues is thus expected. Intracellular trafficking may be favored too, especially as plasmid DNA itself was shown to be immobile in the cytoplasm [6]. Finally, the size of the particles remains compatible with active nuclear pore crossing, which may open the howway
to transfection of post-mitotic cells.