Self-Transfecting Micellar RNA: Modulating Nanoparticle Cell Interactions via High Density Display of Small Molecule Ligands on Micelle Coronas

Bioconjugate Chemistry
Alexander RoloffNathan C Gianneschi

Abstract

The intracellular delivery of synthetic nucleic acids represents a major challenge in biotechnology and in biomedicine. Methods to deliver short, double-stranded RNA to living cells are of particular interest because of the potential to engage the RNA interference machinery and to regulate mRNA expression. In this work, we describe novel RNA-polymer amphiphiles that assemble into spherical micellar nanoparticles with diameters of ca. 15-30 nm and efficiently enter live cells without transfection reagents. Each micelle consists of approximately 100 RNA strands forming a densely packed corona around a polymeric core. Importantly, the surface-displayed RNA remains accessible for hybridization with complementary RNA. Chemical modification of the termini of hybridized RNA strands enabled the display of small organic moieties on the outer surface of the micelle corona. We found that some of these modifications can have a tremendous impact on cellular internalization efficiencies. The display of hydrophobic dabcyl or stilbene units dramatically increased cell uptake, whereas hydrophilic neutral hydroxy or anionic phosphate residues were ineffective. Interestingly, neither of these modifications mediated noticeable uptake of free RNA o...Continue Reading

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