Cationic lipid–DNA complexes for non-viral gene therapy: relating supramolecular structures to cellular pathways

Abstract

Cationic liposomes (CLs) are used as nonviral vectors in worldwide human clinical trials of gene therapy. Among other advantages, lipid–DNA complexes have the ability to transfer very large genes into cells, but their efficiency is much lower than that of viruses. Recent studies combining structural and biological techniques are beginning to unravel the relationship between the distinctly structured CL–DNA complexes and their transfection efficiency. Most CL–DNA complexes form a multilayered structure with DNA sandwiched between the cationic lipids (lamellar complexes, L_α^C). On rare occasions, an inverted hexagonal structure (H_II^C) is observed. An important recent insight is that the membrane charge density (σ_M) of the CL-vector is a universal parameter governing the transfection efficiency of L_α^C (but not H_II^C) complexes. This has led to a new model of the cellular uptake of L_α^C complexes through activated fusion with endosomal membranes. Surface-functionalised complexes with poly(ethylene glycol)-lipids, potentially suitable for transfection invivo, have also been investigated, and the novel aspects of these complexes are discussed.

• cationic liposomes
• gene delivery
• gene therapy
• lipofection
• multivalent
• non-viral
• small-angle X-ray scattering