Molecular Origins of pH Responsiveness in Oleic Acid Nanocarriers: Roles of Headgroup Chemistry and Diolein Positional Isomerism
Abstract
In the development of cancer nanomedicines, pH-responsive nonlamellar liquid crystalline (LLC) nanocarriers are promising platforms owing to their internal architectures responsive to local pH changes in tumor microenvironments. However, their rational design is hampered by insufficient understanding of how subtle changes in amphiphile structure affect their structural features and physicochemical properties. Here, binary mixtures of oleic acid (OA) with either 1,2-diolein or 1,3diolein were used to establish a new family of pH-responsive nanodispersions and investigate the combined effects of OA headgroup chemistry, pH, and diolein positional isomerism on their structural, morphological, and size characteristics. Small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and coarse-grained molecular dynamics simulations were used to characterize the nanodispersions and clarify the driving forces underlying the observed colloidal transformations. At pH 9.0 and 10.0, replacing 1,2-diolein with 1,3-diolein induced a hexosome-to-micellar cubosome transformation, indicating that binary 1,3-diolein/OA nanodispersions favor internal nanostructures with negative spontaneous curvature at pH > 8.0. These nanodispersions also exhibited distinct pH-responsive behavior in the absence and presence of Pluronic F127. Without stabilizer, 1,2-diolein/OA nanodispersions underwent an internal H 2 -to-cubic Fd3m transition upon decreasing pH from 9.0 to 8.0, whereas 1,3-diolein/OA nanodispersions retained an internal cubic Fd3m phase. With Pluronic F127, these nanodispersions exhibited pH-triggered cubic Fd3m-to-L 2 phase transitions, but at different pH values. These results demonstrate that headgroup differences between 2OHOA and OA and diolein positional isomerism govern LLC nanocarrier structure through intermolecular interactions and ionization, supporting the rational design of pH-responsive lipid nanocarriers for cancer drug delivery.
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BibTeX
@misc{wu2026molecular,
title = {{Molecular Origins of pH Responsiveness in Oleic Acid Nanocarriers: Roles of Headgroup Chemistry and Diolein Positional Isomerism}},
author = {Chenyang Wu and Mariana Valerio and Weria Pezeshkian and Huiling Mu and Paulo Cesar Telles de Souza and Anan Yaghmur},
howpublished = {HAL},
year = {2026},
month = oct,
url = {https://hal.science/hal-05787668v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - Molecular Origins of pH Responsiveness in Oleic Acid Nanocarriers: Roles of Headgroup Chemistry and Diolein Positional Isomerism
AU - Chenyang Wu
AU - Mariana Valerio
AU - Weria Pezeshkian
AU - Huiling Mu
AU - Paulo Cesar Telles de Souza
AU - Anan Yaghmur
PY - 2026
DA - 2026/10/08
PB - HAL
UR - https://hal.science/hal-05787668v1
AB - In the development of cancer nanomedicines, pH-responsive nonlamellar liquid crystalline (LLC) nanocarriers are promising platforms owing to their internal architectures responsive to local pH changes in tumor microenvironments. However, their rational design is hampered by insufficient understanding of how subtle changes in amphiphile structure affect their structural features and physicochemical properties. Here, binary mixtures of oleic acid (OA) with either 1,2-diolein or 1,3diolein were used to establish a new family of pH-responsive nanodispersions and investigate the combined effects of OA headgroup chemistry, pH, and diolein positional isomerism on their structural, morphological, and size characteristics. Small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), cryogenic transmission electron microscopy (cryo-TEM), and coarse-grained molecular dynamics simulations were used to characterize the nanodispersions and clarify the driving forces underlying the observed colloidal transformations. At pH 9.0 and 10.0, replacing 1,2-diolein with 1,3-diolein induced a hexosome-to-micellar cubosome transformation, indicating that binary 1,3-diolein/OA nanodispersions favor internal nanostructures with negative spontaneous curvature at pH > 8.0. These nanodispersions also exhibited distinct pH-responsive behavior in the absence and presence of Pluronic F127. Without stabilizer, 1,2-diolein/OA nanodispersions underwent an internal H 2 -to-cubic Fd3m transition upon decreasing pH from 9.0 to 8.0, whereas 1,3-diolein/OA nanodispersions retained an internal cubic Fd3m phase. With Pluronic F127, these nanodispersions exhibited pH-triggered cubic Fd3m-to-L 2 phase transitions, but at different pH values. These results demonstrate that headgroup differences between 2OHOA and OA and diolein positional isomerism govern LLC nanocarrier structure through intermolecular interactions and ionization, supporting the rational design of pH-responsive lipid nanocarriers for cancer drug delivery.
ER -