Effect of cholesterol on nanoparticle translocation across a lipid bilayer

Nanoparticles (NPs) have attracted significant attention as carriers for the delivery of drugs, genes, and macromolecules for biomedical and therapeutic applications. These technologies require NPs to be delivered to the interior of the cell. However, this translocation is unlikely because of the presence of a cell membrane composed of phospholipids, cholesterol, proteins, and glycans. The cell membrane composition can influence its rigidity; thus, membrane composition is a crucial factor in determining the translocation of NPs across the cell membrane. Here, we focus on cholesterol, which is an essential component of biological cell membranes, and investigate NP translocation across membranes containing cholesterol under an applied electric field using a coarse-grained molecular dynamics simulation. We found that NPs could translocate directly across cholesterol-containing membranes without irreversible membrane disruption. This unique translocation was induced by two key phenomena. Before NP translocation, a phospholipid-rich/cholesterol-poor domain was formed at the NP-membrane contact interface. Second, a smaller transmembrane pore was formed in the cholesterol-containing membrane during membrane crossing of the NP. Our findings imply that the delivery of NPs to the cell interior across the cholesterol-containing membrane can be achieved by appropriately controlling the strength of the applied electric field, depending on the cholesterol content in the membrane. Nanoparticle translocation across a cholesterol-containing membrane induced by a unique domain at the contact interface.