Spherical Nucleic Acids: Turning Synthetic Advances and Fundamental Discovery into Translational Breakthroughs in Chemistry, Materials Development, Biology, and Medicine.

Early research in nanoscience and nanotechnology focused on gaining synthetic control over the size, shape, and composition of nanostructures, as well as exploring their fundamental properties. Over the past few decades, these capabilities have become increasingly sophisticated. Today, we have well-established synthetic toolkits and methodologies that enable the design of nanostructures with tailored properties and functions, guided by sets of design rules, for use in many areas spanning biology and medicine to energy, the environment, and catalysis. To illustrate this paradigm, where synthesis and fundamental discovery drive engineering and technological innovation, we examine spherical nucleic acids (SNAs) as a case study. SNAs are nanoconstructs consisting of a nanoparticle core densely functionalized with a radially oriented oligonucleotide shell. Over the past 30 years, the evolution of SNAs has spanned their invention, the development of increasingly advanced syntheses enabling the creation of dozens of SNA classes (and related DNA-functionalized anisotropic materials, often termed programmable atom equivalents [PAEs]), the discovery of novel phenomena that have reshaped core chemical principles, and their translation into nanomedicines, biological labels, and synthons in materials science. SNAs were first developed in 1996 as gold nanoparticle-DNA conjugates. Since then, extensive study has revealed common structural features that are tied to their unique properties, defining SNAs as a distinct materials class. Most SNAs feature a core (typically a nanoparticle, though recent advances involve molecular scaffolds) that concentrate nucleic acid strands into close proximity. This architecture confers several distinctive properties: enhanced binding affinity to complementary DNA (both free and surface-bound), resistance to enzymatic degradation, reduced immune activation (unless specifically designed for immunostimulation), and efficient cellular uptake without requiring transfection agents. These synthetic and fundamental advances offer significant advantages in biomedical probe and therapeutic design. Due to their modularity, stability, biocompatibility, and ability to access intracellular compartments, SNAs have been applied as intracellular and extracellular probes, tools for gene regulation, vaccines, and gene editing platforms (especially when coupled with CRISPR/Cas9 technology). In parallel, SNAs serve as foundational elements in a new class of programmable matter: DNA-mediated colloidal crystals. Here, sequence-specific DNA interactions are used to organize SNAs into three-dimensional, periodic structures. This line of inquiry has enabled the design and synthesis of thousands of crystal variations, with different lattice symmetries, parameters, and nanoparticle compositions, unlocking the potential for novel optical and mechanical metamaterials and catalysts with exceptional properties, such as negative refractive indices, shape memory, and second harmonic generation. In sum, SNAs exemplify how synthetic mastery and fundamental discovery can catalyze innovation across disciplines, providing a framework that chemists can use in developing transformative new materials.