Abstract
Self-assembled DNA delivery systems based on cationic lipids are simple to produce and weakly hazardous in comparison with viral vectors, but possess a significant toxicity at high doses. Phospholipids are in contrast intrinsically safe; yet their association with DNA is problematic because of unfavorable electrostatic interactions. We achieve the phospholipid-DNA complexation through the like-charge attraction induced by cations. Monovalent cations are inappropriate due to their poor binding affinity with lipids as inferred from electrophoretic mobility, whereas x-ray diffractions reveal that with multivalent cations, DNA is complexed within an inverted hexagonal liquid-crystalline phase. Coarse-grained Monte Carlo simulations confirm the self-assembly of a DNA rod wrapped into a lipid layer with cations in between acting as molecular glue. Transfection experiments performed with Ca2+ and La3+ demonstrate efficiencies surpassing those obtained with optimized cationic DOTAP-based systems, while preserving the viability of cells. Inspired by bacteriophages that resort to polycations to compact their genetic materials, complexes assembled with tetravalent spermine achieve unprecedented transfection efficiencies for phospholipids. Influence of complex growth time, lipid/DNA mass ratio, and ion concentration are examined. These complexes may initiate new developments for nontoxic gene delivery and fundamental studies of biological self-assembly.
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