The Modulatory Role of Positional Isomerism in Diolein on the Structural Features of pH-Responsive 2-Hydroxyoleic Acid Nanocarriers

pH-responsive nonlamellar liquid crystalline nano-self-assemblies are gaining substantial interest in drug delivery applications owing to their unique inherent structural architectures. Using two positional isomers of diolein (namely, 1,2-diolein and 1,3-diolein) and their mixture (designated as diolein) in combination with 2-hydroxyoleic acid (2OHOA, a therapeutic agent with anticancer activity), we report on a family of stabilizer-free and pH-responsive nanoparticles with internal architectures spanning from a lamellar (L_α) phase to inverse hexagonal (H₂) and discontinuous (micellar) cubic <i>Fd3m</i> phases. In lipid composition- and pH-dependent manners, the triggered colloidal transformations in these aqueous nanodispersions, combined with alterations in the morphological features and size distributions, were investigated by small-angle X-ray scattering, cryo-transmission electron microscopy, and nanoparticle tracking analysis. The experimental findings support the notion that molecular shapes of lipids, deprotonation/protonation of ionizable lipids, and mutual lipid-lipid and lipid-water interactions at the interfacial area play crucial roles in modulating the biophysical properties of lyotropic liquid crystalline nano-self-assemblies. We discuss how the positional isomerism of diolein can dictate the structural features of the nanoparticles by controlling the interaction modes of diolein with 2OHOA in the interfacial area. Further, the potential of these structurally tunable nanoplatforms in the future development of nanomedicines for the delivery of 2OHOA alone or in combination with other therapeutic agents is highlighted.