Lipid-Nucleic Acid Supramolecular Complexes: Lipoplex Structure and the Kinetics of Formation

The need for synthetic gene therapy or gene silencing vehicles that can insert therapeutic nucleic acids (DNA or siRNA) into cells (so-called transfection) has focused interest on lipid-nucleic acid assemblies (lipoplexes). This paper reviews the kinetics pathways leading to lipoplex formation and structure. The process is qualitatively comparable to those of cluster nucleation and growth and to the adsorption of polyelectrolytes on colloidal particles: Initially is a rapid stage where the nucleic acid binds onto the surface of the cationic lipid aggregate (adsorption, or nucleation). This is followed by an intermediate step where the lipid/nucleic acid complexes flocculate to form larger structures (growth). The last and final step involves internal rearrangement, where the overall global structure remains constant while local adjustment of the nucleic acid/lipid organization takes place until the equilibrium lipoplex characteristics are obtained. This step can require unusually long time scales of order hours or longer. Understanding the kinetics of lipoplex formation is not only of fundamental interest as a multi-component, multi-length scale and multi-time scale process, but also has significant implications for the utilization of lipoplexes as carriers for gene delivery and gene silencing agents.