Structural characterization of the lipid exchange between lipidic cubic phase nanoparticles and lipid monolayers...

Cubosomes are self-assembled lipid nanoparticles with a unique structure that hold significant promise for drug delivery. Cubosomes can encapsulate and transport a wide range of pharmaceuticals and imaging agents, potentially enhancing targeted therapies and medical imaging applications. Although there is growing interest in using cubosomes as drug delivery vehicles, their interactions with biological membranes and their uptake mechanisms remain largely unexplored. The novel methodological approach used in this paper is the combination of neutron reflectometry with Brewster angle microscopy in a Langmuir trough where the surface pressure is monitored in situ during the interaction process. This combined approach allowed us to resolve how phytantriol (PT)-based cubosomes interact with a single leaflet of bilayer membrane represented by the phospholipid monolayer at the air-water interface. Specifically, we used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (sodium salt) (DMPS), emphasizing differences in physicochemical properties including phase of the acyl chains and charge of the headgroup. The relaxation/penetration of the phospholipid monolayers reflected the differences in the nature of these two types of monolayers and their relaxation kinetics. We demonstrate that lipid exchange takes place at the air-water interface between PT-based cubosomes and the model phospholipid membranes. Our approach allows quantification of lipid exchange showing that the extent of lipid exchange depends on phospholipid type, with greater exchange occurring in the negatively charged DMPS monolayers than in zwitterionic DPPC monolayers. This finding shows that the negatively charged headgroups of DMPS, in comparison with DPPC, fosters a different and more dynamic interaction mechanism. The work lays the foundation for the optimization of the formulation of drug delivery carriers based on extended membrane interactions inferred from greater lipid exchange dynamics.