Nanoparticles (NPs) have been attracting much attention for biomedical and pharmaceutical applications. In most of the applications, NPs are required to translocate across the cell membrane and to reach the cell cytosol. Experimental studies have reported that by applying an electric field NPs can directly permeate across the cell membrane without the confinement of NPs by endocytic vesicles. However, damage to the cell can often be a concern. Understanding of the mechanism underlying the direct permeation of NPs under an external electric field can greatly contribute to the realization of a technology for the direct delivery of NPs. Here we investigated the permeation of a cationic gold NP across a phospholipid bilayer under an external electric field using a coarse-grained molecular dynamics simulation. When an external electric field that is equal to the membrane breakdown intensity was applied, a typical NP delivery by electroporation was shown: the cationic gold NP directly permeated across a lipid bilayer without membrane wrapping of the NP, while a persistent transmembrane pore was formed. However, when a specific range of the electric field that is lower than the membrane breakdown intensity was applied, a unique permeation pathway was exhibited: the generated transmembrane pore immediately resealed after the direct permeation of NP. Furthermore, we found that the affinity of the NP for the membrane surface is a key for the self-resealing of the pore. Our finding suggests that by applying an electric field in a suitable range NPs can be directly delivered into the cell with less cellular damage.

Nanoparticles have attracted much attention as a key material for new biomedical and pharmaceutical applications. For success in these applications, the nanoparticles are required to translocate across the cell membrane and to reach to inside of the cell. Among several translocation pathways of nanoparticles, the direct permeation pathway has a great advantage due to its high delivery efficacy. However, despite many research efforts, key properties and factors for driving the direct permeation of nanoparticle and its underlying mechanisms are far from being understood. In this article, experimental and computational studies regarding the direct permeation of nanoparticles across a cell membrane will be reviewed. Firstly, experimental studies on the nanoparticle-cell interactions, where spontaneous direct permeation of nanoparticles was observed, are reviewed. From the experimental studies, potential key physico-chemical properties of nanoparticles for their direct permeation are discussed. Secondly, physical methods such as electroporation and sonoporation for delivering nanoparticles into cells are reviewed. Current status of technologies for facilitating the direct permeation of nanoparticle is presented. Finally, we review molecular dynamics simulation studies and present the latest findings on the underlying molecular mechanisms of the direct permeation of nanoparticle.

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Magnetite nanoparticles were prepared by hydrothermal synthesis under various initial ferrous/ferric molar ratios without adding any oxidizing and reducing agents in order to clarify effects of the molar ratio on the reaction mechanism for the formation of magnetite nanoparticles. The magnetite nanoparticles prepared were characterized by a scanning electron microscope, powder X-ray diffractometer, and superconducting quantum interference device (SQUID). At the molar ratio corresponding to the stoichiometric ratio in the synthesis reaction of magnetite from ferrous hydroxide and goethite, the nucleation of magnetite crystals progressed rapidly in an initial stage of the hydrothermal synthesis, resulting in formation of the magnetite nanoparticles having a smaller size and a lower crystallinity. On the other hand, at higher molar ratios, the particle size and crystallinity increased with increasing molar ratio because using surplus ferrous hydroxide the crystallites of magnetite nanoparticles grew up slowly under hydrothermal conditions according to the Schikorr reaction. The magnetite nanoparticles prepared under various molar ratios had good magnetic properties regardless of the molar ratio.

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