Abstract: Spherical nucleic acids (SNAs), consisting of densely packed, highly oriented polynucleotide strands attached to the surface of nanoparticles, are able to overcome the typical challenges of nucleic acid delivery. The present disclosure demonstrates that G-rich SNAs exhibit several-fold higher uptake into cells relative to SNAs rich in other nucleotides. This disclosure provides an effective strategy to maximize the intracellular delivery of SNAs, which is applicable to other nanoparticle systems, thus establishing an important design consideration for nanoparticle-based intracellular delivery of therapeutics.