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Complexes of cationic and neutral lipids and DNA (lipoplexes) are emerging aspromising vectors for gene therapy applications. Their appeal stems from theirnon pathogenic nature and the fact that they self-assemble under conditions ofthermal equilibrium. Lipoplex adhesion to the cell plasma membrane initiates athree-stage process termed transfection, consisting of (i) endocytosis, (ii)lipoplex breakdown, and (iii) DNA release followed by gene expression. Assuccessful transfection requires lipoplex degradation, it tends to be hinderedby the lipoplex thermodynamic stability; nevertheless, it is known that thetransfection process may proceed spontaneously. Here, we use a simple model tostudy the thermodynamic driving forces governing transfection. We demonstratethat after endocytosis [stage (i)], the lipoplex becomes inherently unstable.This instability, which is triggered by interactions between the cationiclipids of the lipoplex and the anionic lipids of the enveloping plasmamembrane, is entropically controlled involving both remixing of the lipids andcounterions release. Our detailed calculation shows that the free energy gainduring stage (ii) is approximately linear in $\Phi_+$, the mole fraction ofcationic lipids in the lipoplex. This free energy gain, $\Delta F$, reduces thebarrier for fusion between the enveloping and the lipoplex bilayers, whichproduces a hole allowing for DNA release [stage (iii)]. The linear relationshipbetween $\Delta F$ and the fraction of cationic lipids explains theexperimentally observed exponential increase of transfection efficiency with$\Phi_+$ in lamellar lipoplexes.

The Thermodynamics of Endosomal Escape and DNA Release from Lipoplexes