Remarkably Size-Regulated Cell Invasion by Artificial Viruses. Saccharide-Dependent Self-Aggregation of Glycoviruses and Its Consequences in Glycoviral Gene Delivery

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Abstract
We here report a novel example of artificial glycoviral vectors constructed via number- and size-controlled gene (pCMVluc, 7040 bp) coating with micellar glycocluster nanoparticles (GNPs) of calix[4]resorcarene-based macrocyclic glycocluster amphiphiles having eight or five saccharide moieties with terminal α-glucose (α-Glc), β-glucose (β-Glc), or β-galactose (β-Gal) residues. The resulting glycoviruses are compactly packed (∼50 nm) and well charge-shielded (ζ ≅ 0 mV), undergo saccharide-dependent (α-Glc > β-Gal ≫ β-Glc) self-aggregation, and transfect cell (Hela and HepG2) cultures as triggered by the pinocytic form of endocytosis. The semilogarithmic linear size−activity correlation suggests that size-restricted pinocytosis (2-times higher than expected on the size basis, owing to the receptor-mediated specific pathway involving the asialoglycoprotein receptors on the hepatic cell surfaces. The scope and prospect of artificial glycoviruses are discussed.