The natural defenses of biological systems for exogenous oligonucleotides, such as synthetic antisense DNA and siRNA, present many challenges for the delivery of nucleic acids in an efficient, non-toxic, and non-immunogenic fashion. Indeed, because nucleic acids are negatively charged and prone to enzymatic degradation, researchers have historically relied on transfection agents such as cationic polymers, liposomes, and modified viruses to facilitate cellular entry and protect delivered biomolecules from degradation. However, each of these platforms is subject to several drawbacks, which include toxicity at high concentrations, the requirement of specialty nucleic acids to enhance stability, and severe immunogenicity.            Spherical nucleic acid (SNA) gold nanoparticle conjugates (inorganic nanoparticle cores functionalized with a spherical shell of densely organized, highly oriented nucleic acids) pose one possible solution for circumventing these problems in the context of both antisense and RNAi pathways. Remarkably, these highly negatively charged SNA structures do not require cationic transfection agents or additional particle surface modifications and naturally enter all cell lines tested to date (over 50, including primary cells). Further work has shown the cellular uptake of these particles to be dependent upon DNA surface density: higher densities lead to higher levels of particle uptake. The high-density polyvalent nucleic acid surface layer is believed to recruit scavenger receptors from the cells that facilitate endocytosis. Moreover, the ion cloud associated with the high-density oligonucleotide shell, combined with steric inhibition at the surface of the particles, inhibits enzymatic nucleic acid degradation and activation of the enzymes that trigger the innate immune response of certain cells. In this talk, methods to synthesize such structures and novel applications that take advantage of the interesting properties unique to spherical and other forms of three-dimensional nucleic acids will be described.

Spherical nucleic acid (SNA) nanostructures: Establishing a new paradigm in molecular diagnostics and intracellular gene regulation

247th National Meeting (2014)

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