page_title: Spherical nucleic acid
section_title: Structure and Function
hierarchical_section_title: Spherical nucleic acid / Structure and Function
caption_attribution_description: English: Adapted from Cutler, J. I., et al., Spherical Nucleic Acids. J Am Chem Soc 2012, 134 (3), 1376-1391. Copyright 2012 American Chemical Society.
context_page_description: Spherical nucleic acids are nanostructures that consist of a densely packed, highly oriented arrangement of linear nucleic acids in a three-dimensional, spherical geometry. This novel three-dimensional architecture is responsible for many of the SNA's novel chemical, biological, and physical properties that make it useful in biomedicine and materials synthesis. SNAs were first introduced in 1996 by Chad Mirkin’s group at Northwestern University.
context_section_description: The SNA structure typically consists of two components: a nanoparticle core and a nucleic acid shell. The nucleic acid shell is made up of short, synthetic oligonucleotides terminated with a functional group that can be utilized to attach them to the nanoparticle core. The dense loading of nucleic acids on the particle surface results in a characteristic radial orientation around the nanoparticle core, which minimizes repulsion between the negatively charged oligonucleotides.
  The first SNA consisted of a gold nanoparticle core with a dense shell of 3’ alkanethiol-terminated DNA strands. Repeated additions of salt counterions were used to reduce the electrostatic repulsion between DNA strands and enable more efficient DNA packing on the nanoparticle surface. Since then, silver, iron oxide, silica, and semiconductor materials have also been used as inorganic cores for SNAs. Other core materials with increased biocompatibility, such FDA-approved PLGA polymer nanoparticles, micelles, liposomes, and proteins have also been used to prepare SNAs. Single-stranded and double-stranded versions of these materials have been created using, for example, DNA, LNA, and RNA.
  One- and two-dimensional forms of nucleic acids (e.g., single strands, linear duplexes, and plasmids) (Fig. 1) are important biological machinery for the storage and transmission of genetic information. The specificity of DNA interactions through Watson-Crick base pairing provides the foundation for these functions. Scientists and engineers have been synthesizing and, in certain cases, mass-producing nucleic acids for decades to understand and exploit this elegant chemical recognition motif. The recognition abilities of nucleic acids can be enhanced when arranged in a spherical geometry, which allows for polyvalent interactions to occur. This polyvalency, along with the high density and degree of orientation described above, helps explain why SNAs exhibit different properties than their lower-dimensional constituents (Fig. 2).
  Over two decades of research has revealed that the properties of a SNA conjugate are a synergistic combination of those of the core and the shell. The core serves two purposes: 1) it imparts upon the conjugate novel physical and chemical properties (e.g., plasmonic, catalytic, magnetic, luminescent), and 2) it acts as a scaffold for the assembly and orientation of the nucleic acids. The nucleic acid shell imparts chemical and biological recognition abilities that include a greater binding strength, cooperative melting behavior, higher stability, and enhanced cellular uptake without the use of transfection agents (compared to the same sequence of linear DNA). It has been shown that one can crosslink the DNA strands at their base, and subsequently dissolve the inorganic core with KCN or I₂ to create a core-less (hollow) form of SNA (Fig. 3, right), which exhibits many of the same properties as the original polyvalent DNA gold nanoparticle conjugate (Fig. 3, left). 
  Due to their structure and function, SNAs occupy a materials space distinct from DNA nanotechnology and DNA origami, (although both are important to the field of nucleic acid–guided programmable materials). With DNA origami, such structures are synthesized via DNA hybridization events. In contrast, the SNA structure can be synthesized independent of nucleic acid sequence and hybridization, instead their synthesis relies upon chemical bond formation between nanoparticles and DNA ligands. Furthermore, DNA origami uses DNA hybridization interactions to realize a final structure, whereas SNAs and other forms of three-dimensional nucleic acids (anisotropic structures templated with triangular prism, rod, octahedra, or rhombic dodecadhedra-shaped nanoparticles) utilize the nanoparticle core to arrange the linear nucleic acid components into functional forms. It is the particle core that dictates the shape of the SNA. SNAs should also not be confused with their monovalent analogues – individual particles coupled to a single DNA strand. Such single strand-nanoparticle conjugate structures have
caption: Figure 2. Properties of spherical nucleic acids (SNAs) versus linear nucleic acids.[1]
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