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

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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, LαC). On rare occasions, an inverted hexagonal structure (HIIC) is observed. An important recent insight is that the membrane charge density (σM) of the CL-vector is a universal parameter governing the transfection efficiency of LαC (but not HIIC) complexes. This has led to a new model of the cellular uptake of LαC complexes through activated fusion with endosomal membranes. Surface-functionalised complexes with poly(ethylene glycol)-lipids...

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