Polyvalent Nucleic Acid Nanostructures

Cutler, Joshua I.; Zhang, Ke; Zheng, Dewen; Auyeung, Evelyn; Prigodich, Andrew E.; Mirkin, Chad A.

doi:10.1021/ja203375n

Cited by 163 publications

(188 citation statements)

References 36 publications

Supporting

Mentioning

178

Contrasting

Unclassified

Order By: Relevance

“…1D and Dataset S1). These observations are consistent with previous studies in the HeLa cell line, which show that SNA-NCs enter cells in a stealth-like fashion and exhibit limited interference with normal cellular behavior (24,26,27).…”

Section: Resultssupporting

confidence: 93%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

365

288

View full text Add to dashboard Cite

Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNANCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are >100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.T he recent development of small molecule inhibitors and antibodies that target components of signaling pathways has revolutionized the treatment of cancers, inflammatory diseases, and genetic disorders, including those that largely manifest in skin (1-3). These protein-based therapeutics, however, are costly, have limited targeting ability, and, when delivered through traditional intravenous or gastrointestinal routes, can lead to systemic toxicity (4, 5). Topical delivery is particularly attractive for the therapy of skin disorders. However, proteins larger than a few hundred daltons cannot easily enter the skin, and high concentrations of proteins must be applied for a cutaneous effect (6). An alternative to protein-based pathway inhibition involves the blocking and/or degradation of precursor mRNA before translation into protein. Gene silencing leads to down-regulation of protein expression and functions with greater specificity than inhibitors of protein function (7). In fact, targeted gene suppression by antisense DNA and siRNA has shown promising preclinical results, and/or is currently in clinical trials for a variety of diseases, including many forms of cancer (e.g., melanoma, neuroblastoma, and pancreatic adenocarcinoma), genetic disorders, and macular degeneration (8). For gene su...

show abstract

Section: Resultssupporting

confidence: 93%

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Zheng

Giljohann

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

365

288

View full text Add to dashboard Cite

show abstract

“…For that purpose the ODN was attached via a propargyl ether-modified terminal nucleotide on an Au NP template and cross-linked. Finally, the core was removed by oxidative dissolution [107].…”

Section: Dna-au Npsmentioning

confidence: 99%

Drug delivery systems based on nucleic acid nanostructures

Vries

Zhang

Herrmann

2013

Journal of Controlled Release

View full text Add to dashboard Cite

a b s t r a c t a r t i c l e i n f oThe field of DNA nanotechnology has progressed rapidly in recent years and hence a large variety of 1D-, 2D-and 3D DNA nanostructures with various sizes, geometries and shapes is readily accessible. DNA-based nanoobjects are fabricated by straight forward design and self-assembly processes allowing the exact positioning of functional moieties and the integration of other materials. At the same time some of these nanosystems are characterized by a low toxicity profile. As a consequence, the use of these architectures in a biomedical context has been explored. In this review the progress and possibilities of pristine nucleic acid nanostructures and DNA hybrid materials for drug delivery will be discussed. For the latter class of structures, a distinction is made between carriers with an inorganic core composed of gold or silica and amphiphilic DNA block copolymers that exhibit a soft hydrophobic interior.

show abstract

“…[14][15][16][17][18] Despite the rapid progress, most of these applications used polyvalent DNA-AuNP conjugates without knowing the exact number of loaded DNA strands. Although polyvalent DNA-AuNPs possess unique merits, such as signal amplification and cellular internalization; [19][20][21] such inaccuracy may introduce potential imperfectness in the artificially constructed nanosystems.…”

Section: Introductionmentioning

confidence: 99%

Clicking DNA to gold nanoparticles: poly-adenine-mediated formation of monovalent DNA-gold nanoparticle conjugates with nearly quantitative yield

et al. 2015

View full text Add to dashboard Cite

Monovalent DNA-gold nanoparticle (mDNA-AuNP) conjugates hold great promise for widespread applications, especially the construction of well-defined, molecule-like nanosystems. Previously reported methods all rely on the use of thiolated DNA to functionalize AuNPs, resulting in relatively low yields. Here, we report a facile method to rapidly prepare mDNA-AuNPs using a poly-adenine (polyA)-mediated approach. As polyA can selectively bind to AuNPs with high controllability of the surface density of DNA, we can use a DNA strand with a sufficiently long polyA to wrap around the surface of an individual AuNP, preventing further the adsorption of additional strands. Based on this observation, we obtained mDNA-AuNPs with a nearly quantitative yield of~90% using 80 As, as confirmed by both gel electrophoresis and transmission electron microscope observation. The yields of mDNA-AuNPs were insensitive to the stoichiometric ratio between DNA and AuNPs, suggesting the click chemistry-like nature of this polyA-mediated reaction. mDNA-AuNPs exhibited rapid kinetics and high efficiency for sequence-specific hybridization. More importantly, we demonstrated that AuNPs of fixed valences could form well-defined heterogenous oligomeric nanostructures with precise, atom-like control.

show abstract

Polyvalent Nucleic Acid Nanostructures

Cited by 163 publications

References 36 publications

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation

Drug delivery systems based on nucleic acid nanostructures

Clicking DNA to gold nanoparticles: poly-adenine-mediated formation of monovalent DNA-gold nanoparticle conjugates with nearly quantitative yield

Contact Info

Product

Resources

About