How Real‐Time Kinetics Explain the Different Interaction of Cubosomes and Hexosomes Nanoparticles with Lipid Membranes

Cubosomes and hexosomes are interesting structures with diverse applications as drug and gene delivery systems, as well as theranostics. Understanding the uptake mechanism of these nanostructures by cell membranes is fundamental to improving and broadening their application. In this study, the kinetics of interaction of monoolein (GMO) cubosomes or dioleoylphosphatidylethanolamine (DOPE) hexosomes with supported lipid bilayers (SLBs) with varying compositions and stiffness, as valuable model membranes, are investigated by neutron reflectivity (NR) coupled with quartz crystal microbalance with dissipation monitoring (QCM‐D). Atomic force microscopy (AFM) is also used to analyze SLBs topography after such interaction. Cubosomes rapidly interact with SLBs, resulting in lipid exchange between the two systems, destabilizing the bilayer, and ultimately causing its removal. The inclusion of cholesterol (CHOL) in the SLB confers rigidity, making it more resistant to removal. Completely different results are obtained when hexosomes interact with SLBs: an intrinsic resistance of the bilayers toward these nanoparticles is observed, regardless of CHOL presence, combined with a slight change in SLB composition, suggesting that hexosomes tend to fuse with the SLB. These findings provide new and valuable insights into the potential mechanisms and kinetics of cellular uptake of these systems, enhancing their potential as drug delivery vectors.