Precisely tunable engineering of sub-30 nm monodisperse oligonucleotide nanoparticles

Advancement of RNAi therapies is mainly hindered by the development of efficient delivery vehicles. The ability to create small size (<30 nm) oligonucleotide nanoparticles is essential for many aspects of the delivery process but is often overlooked. In this report, we describe diblock star polymers that can reproducibly complex double-stranded oligonucleotides into monodisperse nanoparticles with 15, 23, or 30 nm in diameter. The polymer-nucleic acid nanoparticles have a core-shell architecture with dense PEG brush coating. We characterized these nanoparticles using ITC, DLS, FRET, FCS, TIRF, and TEM. In addition to small size, these nanoparticles have neutral zeta-potentials, making the presented polymer architecture a very attractive platform for investigation of yet poorly studied polyplex size range for siRNA and antisense oligonucleotide delivery applications.