Cationic liposome–nucleic acid complexes: Liquid crystal phases with applications in gene therapy

Cationic liposome (CL) carriers of nucleic acids are studied primarily because of their applications in gene delivery and gene silencing with CL-DNA and CL-siRNA (short-interfering RNA) complexes, respectively, and their implications for ongoing clinical gene therapy trials worldwide. A series of synchrotron-based small-angle X-ray scattering studies, dating back to 1997, has revealed that CL-nucleic acid complexes spontaneously assemble into distinct novel liquid crystalline phases of matter. Significantly, transfection efficiency (TE; a measure of expression of an exogenous gene that is transferred into the cell by the lipid carrier) has been found to be dependent on the liquid crystalline structure of complexes, with lamellar complexes showing strong dependence on membrane charge density (σM) and non-lamellar complexes exhibiting TE behaviour independent of σM. The review describes our current understanding of the structures of different liquid crystalline CL-nucleic acid complexes including the recently described gyroid cubic phase of CL-siRNA complexes used in gene silencing. It further makes apparent that the long-term goal of developing optimised liquid crystalline CL-nucleic acid complexes for successful medical applications requires a comprehensive understanding of the nature of the interactions of distinctly structured complexes with cell membranes and events leading to release of active nucleic acids within the cell cytoplasm.