FIGURE 3.

(A) Bligh–Dyer (BD) tunable solvents as modulators of the phobic–philic trade-off controllable under a compatibilizer (methanol: MeOH), which enables for tuning the dielectric BD permittivity ( ${ϵ}_{BD}$ ). The canonical BD solvent is a monophase that combines oil (chloroform) and water with a content of MeOH compatibilizer (1Φ), close or higher than a critical composition (ca. 55% chloroform; 30% water; and 15% methanol). BD mixtures with a poor content in methanol segregate into two phases (2Φ); the rich-in-water, high-permittivity BD solvent containing hydrophilic components (light phase; upper) and the “maximum” chloroform, low-permittivity BD phase that allows for extracting the most hydrophobic components (heavy phase; lower). The material exchange of components happens through the “tie-line” interface, which stabilizes the spinodal decomposition between the BD phases upon depleting the BD compatibilizer (MeOH). (B) Phase BD diagram as constituted by the ternary mixture H₂O/CHCl₃/MeOH. The liquid percentages are expressed in weight per weight (% w/w), as adapted from the original article (Kebbekus et al., 1995). The blue line represents the phase separation (1Φ→2Φ) binodal boundary. We followed a two-step procedure to transfer GR and DChol from water-rich media into a low-permittivity electrostatic environment with a highly condensing (Manning-like) lipoplexing capacity (see Figure 2, and explanation in main text for details). Phase segregation occurs as spinodal decompositions along tie-lines. We chose directions toward a maximum chloroform line in the biphasic region (magenta dashed line), which allows partitioning of hydrophilic components into the aqueous upper layer (essentially water–methanol), and hydrophobic, non-polar, neutral components such as most lipids and GR-DChol lipoplexes into an organic phase as a chloroform-rich heavy layer. Both layers are colloidally nanostructured close to the critical point (Kebbekus et al., 1995), a fact here exploited to the best extraction efficiency of the most condensed components into drop-templated nanoparticles. The organic “maximum chloroform” BD layer is an efficient host for extracting the neutral catanionic aggregates, independent of their intrinsic hydrophilicity, whereas the water-rich layer requires less cost in free energy to insert non-complexed GRs and non-aggregated polar components.