The natural defenses of biological systems for exogenous nucleic acids (e.g., synthetic DNA and siRNA) present many challenges to the efficient, non-toxic, and non-immunogenic intracellular delivery of these moieties for diagnostic and therapeutic purposes. 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 drawbacks, including toxicity at high concentrations, the requirement of specialty nucleic acids to enhance stability, and severe immunogenicity.We have invented and developed a new type of material that circumvents all of these issues - spherical nucleic acid (SNA)-gold nanoparticle conjugates (inorganic nanoparticle cores functionalized with a shell of densely packed, highly oriented nucleic acids). Remarkably, these highly negatively charged SNA structures do not require cationic transfection agents or additional particle surface modification to naturally enter all cell lines tested to date (over 50, including primary cells) in high quantities. Using coreless versions of these SNAs, we have unequivocally proven that the novel properties of these structures, including their efficient cellular uptake and their ability to inactivate enzymes which play a role in nucleic acid degradation and innate immune response triggering, are due only to the dense and highly oriented arrangement of the nucleic acids comprising the ligand shell.  Specifically, the use of SNAs in the RNAi-based treatment of high-grade brain tumors (i.e., glioblastoma) and as an agent for the topical delivery of nucleic acids for the treatment of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders will be discussed.

Spherical nucleic acid (SNA) nanostructures: A new platform for intracellular gene regulation

244th National Meeting (2012)

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