Arginine-Terminated Nanoparticles of <10 nm Size for Direct Membrane Penetration and Protein Delivery for Straight Access to Cytosol and Nucleus

Although colloidal nanoparticles are known to enter into cells via endocytosis, the direct membrane permeation of nanoparticles is rarely reported, and the underlying mechanism of direct membrane permeation is largely unsolved. However, a direct membrane-penetrating nanoparticle has great advantage as a delivery carrier that offers high delivery efficiency, faster delivery kinetics, and minimal lysosomal degradation. Here we show that arginine-terminated Au nanoparticles of <10 nm size enter via energy-independent direct membrane penetration, but as the size increases, the nanoparticles switch to energy-dependent endocytotic uptake. As a delivery carrier, <10 nm Au nanoparticles directly transport an electrostatically bound protein into the cytosol within a minute and allow direct access of the protein to subcellular compartments. This direct delivery approach has been used for efficient nuclear targeting of proteins and can be adapted for direct cytosolic delivery or subcellular targeting applications with high efficiency.