Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma.

Glioblastoma multiforme (GBM) is a neurologically debilitating disease that culminates in death 14 to 16 months after diagnosis. An incomplete understanding of how cataloged genetic aberrations promote therapy resistance, combined with ineffective drug delivery to the central nervous system, has rendered GBM incurable. Functional genomics efforts have implicated several oncogenes in GBM pathogenesis but have rarely led to the implementation of targeted therapies. This is partly because many "undruggable" oncogenes cannot be targeted by small molecules or antibodies. We preclinically evaluate an RNA interference (RNAi)-based nanomedicine platform, based on spherical nucleic acid (SNA) nanoparticle conjugates, to neutralize oncogene expression in GBM. SNAs consist of gold nanoparticles covalently functionalized with densely packed, highly oriented small interfering RNA duplexes. In the absence of auxiliary transfection strategies or chemical modifications, SNAs efficiently entered primary and transformed glial cells in vitro. In vivo, the SNAs penetrated the blood-brain barrier and blood-tumor barrier to disseminate throughout xenogeneic glioma explants. SNAs targeting the oncoprotein Bcl2Like12 (Bcl2L12)--an effector caspase and p53 inhibitor overexpressed in GBM relative to normal brain and low-grade astrocytomas--were effective in knocking down endogenous Bcl2L12 mRNA and protein levels, and sensitized glioma cells toward therapy-induced apoptosis by enhancing effector caspase and p53 activity. Further, systemically delivered SNAs reduced Bcl2L12 expression in intracerebral GBM, increased intratumoral apoptosis, and reduced tumor burden and progression in xenografted mice, without adverse side effects. Thus, silencing antiapoptotic signaling using SNAs represents a new approach for systemic RNAi therapy for GBM and possibly other lethal malignancies.

Spherical nucleic acids.

A historical perspective of the development of spherical nucleic acid (SNA) conjugates and other three-dimensional nucleic acid nanostructures is provided. This Perspective details the synthetic methods for preparing them, followed by a discussion of their unique properties and theoretical and experimental models for understanding them. Important examples of technological advances made possible by their fundamental properties spanning the fields of chemistry, molecular diagnostics, gene regulation, medicine, and materials science are also presented.

Synthetically programmable nanoparticle superlattices using a hollow three-dimensional spacer approach.

Crystalline nanoparticle arrays and superlattices with well-defined geometries can be synthesized by using appropriate electrostatic, hydrogen-bonding or biological recognition interactions. Although superlattices with many distinct geometries can be produced using these approaches, the library of achievable lattices could be increased by developing a strategy that allows some of the nanoparticles within a binary lattice to be replaced with 'spacer' entities that are constructed to mimic the behaviour of the nanoparticles they replace, even though they do not contain an inorganic core. The inclusion of these spacer entities within a known binary superlattice would effectively delete one set of nanoparticles without affecting the positions of the other set. Here, we show how hollow DNA nanostructures can be used as 'three-dimensional spacers' within nanoparticle superlattices assembled through programmable DNA interactions. We show that this strategy can be used to form superlattices with five distinct symmetries, including one that has never before been observed in any crystalline material.

Polyvalent nucleic acid nanostructures.

Polyvalent oligonucleotide-nanoparticle conjugates possess several unique emergent properties, including enhanced cellular uptake, high antisense bioactivity, and nuclease resistance, which hypothetically originate from the dense packing and orientation of oligonucleotides on the surface of the nanoparticle. In this Communication, we describe a new class of polyvalent nucleic acid nanostructures (PNANs), which are comprised of only cross-linked and oriented nucleic acids. We demonstrate that these particles are capable of effecting high cellular uptake and gene regulation without the need of a cationic polymer co-carrier. The PNANs also exhibit cooperative binding behavior and nuclease resistance properties.

Nanopod formation through gold nanoparticle templated and catalyzed cross-linking of polymers bearing pendant propargyl ethers.

A novel method for synthesizing polymer nanopods from a linear polymer bearing pendant propargyl ether groups, using gold nanoparticles as both the template and the catalyst for the cross-linking reaction, is reported. The transformations involved in the cross-linking process are unprecedented on the surface of a gold particle. A tentative cross-linking mechanism is proposed.

Polyvalent oligonucleotide iron oxide nanoparticle "click" conjugates.

We have utilized the copper-catalyzed azide-alkyne reaction to form a dense monolayer of oligonucleotides on a superparamagnetic nanoparticle core. These particles exhibit the canonical properties of materials densely functionalized with DNA, which can be controlled by modulating the density of oligonucleotides on the surface of the particles. Furthermore, like their Au analogues, these particles can easily cross HeLa (cervical cancer) cell membranes without transfection agents due to their dense DNA shell. Importantly, this approach should be generalizable to other azide-functionalized particles.

Colloidal gold and silver triangular nanoprisms.

It is now well-known that the size, shape, and composition of nanomaterials can dramatically affect their physical and chemical properties, and that technologies based on nanoscale materials have the potential to revolutionize fields ranging from catalysis to medicine. Among these materials, anisotropic particles are particularly interesting because the decreased symmetry of such particles often leads to new and unusual chemical and physical behavior. Within this class of particles, triangular Au and Ag nanoprisms stand out due to their structure- and environment-dependent optical features, their anisotropic surface energetics, and the emergence of reliable synthetic methods for producing them in bulk quantities with control over their edge lengths and thickness. This Review will describe a variety of solution-based methods for synthesizing Au and Ag triangular prismatic structures, and will address and discuss proposed mechanisms for their formation.