What is Spherical Nucleic Acid?

Spherical Nucleic Acids

Spherical nucleic acids (SNA) are nanostructures of densely packed and highly oriented arrays of linear nucleic acids in a three-dimensional spherical geometry. This new three-dimensional structure defines a new class of nucleic acids with properties that are distinctly different from similar linear (1D) chains of the same sequence. For example, on the basis of a sequence-pair sequence, SNA binds complementary nucleic acids more tightly and enters cells faster and in greater quantities without the use of transfection agents by binding to scavenger receptors that promote folliculin-mediated endocytosis. These capabilities enable the use of SNAs in biological applications spanning extracellular and intracellular assays, gene editing and immunotherapy.

Fig 1. Representative examples of SNA structures. (Song et al., 2022)

Structure of Spherical Nucleic Acids

SNA structures typically consist of two components: a nanoparticle core and a nucleic acid shell. The nucleic acid shell consists of short synthetic oligonucleotides with functional groups at the ends that can be attached to the nanoparticle core. The dense loading of nucleic acids on the particle surface leads to a characteristic radial orientation around the nanoparticle core, which minimizes repulsive forces between negatively charged oligonucleotides.

The core composition of SNA can be gold and silver, iron oxide, silicon dioxide and semiconductor materials. And other core materials with improved biocompatibility, such as PLGA polymer nanoparticles, micelles, liposomes and proteins, have also been used to prepare SNA.

How to Control the Nucleic Acid Density on the SNA Surface?

Further expansion of SNAs depends on their ability to have higher stability and more unique functionalities. These properties are in turn largely determined by the DNA density on the surface of the nanoparticles. A variety of parameters controlling oligonucleotide loading need to be examined: these include the salt concentration of the reaction solution, the size and shape of the nanoparticles, the type of base closest to the surface of the particles, the effect of ultrasonication or heating on the properties of the product, and the characteristics of the chemically attached portion.

Among other things, the maximum density of DNA modified on the surface of nanoparticles depends on the size and shape of the particles. For spherical particles, smaller spherical particles have a greater surface density and are much higher than the maximum density that can be achieved in a planar configuration.

Applications of Spherical Nucleic Acids

• Immunotherapeutic Agents

Due to the properties of SNA, such as enhanced cellular uptake, multivalent binding and endosomal delivery, it is ideal for the delivery of immunomodulatory nucleic acids. In particular, SNA has been used to deliver nucleic acids that agonize or antagonize Toll-like receptors (proteins involved in innate immune signaling). The use of immunostimulatory SNA has resulted in an 80-fold increase in potency, a 700-fold increase in antibody titer, and a 400-fold increase in cellular response to model antigens compared to free oligonucleotides (non-nucleotides).

• Intracellular Probes

An SNA architecture can be utilized for intracellular mRNA detection. In this design, an antisense DNA strand capped with a streptavidin is attached to the surface of gold nanoparticles. A fluorophore hybridizes the labeled "reporter strand" to the SNA construct, and as the fluorophore label approaches the gold surface, their fluorescence is burst under the control of programmable nucleic acid hybridization.

• Intracellular Gene Regulation

SNA can deliver small interfering RNAs (siRNAs) for the treatment of glioblastoma multiforme. SNA targets Bcl2Like12, a gene overexpressed in glioblastomas, to inhibit oncogenes. Intravenous SNA crosses the blood-brain barrier and finds its target in the brain. In animal models, this treatment resulted in a 20% increase in survival and a 3-4 fold reduction in tumor size.

Reference

1. Song Y, et al. Spherical nucleic acids: Organized nucleotide aggregates as versatile nanomedicine[J]. Aggregate, 2022, 3(1): e120.