  Complexes of cationic and neutral lipids and DNA (lipoplexes) are emerging as
promising vectors for gene therapy applications. Their appeal stems from their
non pathogenic nature and the fact that they self-assemble under conditions of
thermal equilibrium. Lipoplex adhesion to the cell plasma membrane initiates a
three-stage process termed transfection, consisting of (i) endocytosis, (ii)
lipoplex breakdown, and (iii) DNA release followed by gene expression. As
successful transfection requires lipoplex degradation, it tends to be hindered
by the lipoplex thermodynamic stability; nevertheless, it is known that the
transfection process may proceed spontaneously. Here, we use a simple model to
study the thermodynamic driving forces governing transfection. We demonstrate
that after endocytosis [stage (i)], the lipoplex becomes inherently unstable.
This instability, which is triggered by interactions between the cationic
lipids of the lipoplex and the anionic lipids of the enveloping plasma
membrane, is entropically controlled involving both remixing of the lipids and
counterions release. Our detailed calculation shows that the free energy gain
during stage (ii) is approximately linear in $\Phi_+$, the mole fraction of
cationic lipids in the lipoplex. This free energy gain, $\Delta F$, reduces the
barrier for fusion between the enveloping and the lipoplex bilayers, which
produces a hole allowing for DNA release [stage (iii)]. The linear relationship
between $\Delta F$ and the fraction of cationic lipids explains the
experimentally observed exponential increase of transfection efficiency with
$\Phi_+$ in lamellar lipoplexes.
