The Sequence‐Specific Cellular Uptake of Spherical Nucleic Acid Nanoparticle Conjugates

Narayan, Suguna P.; Choi, Chung Hang Jonathan; Hao, Liangliang; Calabrese, Colin M.; Auyeung, Evelyn; Zhang, Chuan; Goor, Olga J. G. M.; Mirkin, Chad A.

doi:10.1002/smll.201500027

Cited by 65 publications

(69 citation statements)

References 44 publications

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“…Previous work has shown that SNAs composed of G‐rich oligonucleotide sequences facilitate interactions with both cell‐surface scavenger receptors and a variety of serum proteins due to the enhanced formation of G‐quadruplexes, which is mediated by the dense layer of oligonucleotides that brings preoriented DNA strands in close proximity to one another on the SNA surface. Based upon the enhanced interaction of G‐quadruplex‐forming, G‐rich SNAs with serum proteins, we hypothesized that the protein corona formed on G‐rich SNAs would facilitate their uptake into phagocytic macrophage cells, and that this would lead to subsequent accumulation in the macrophage‐rich liver and spleen in vivo.…”

Section: Resultssupporting

confidence: 83%

The Impact of Protein Corona Formation on the Macrophage Cellular Uptake and Biodistribution of Spherical Nucleic Acids

Chinen

Guan

et al. 2017

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The effect of serum protein adsorption on the biological fate of Spherical Nucleic Acids (SNAs) is investigated. Through a proteomic analysis, it is shown that G-quadruplexes templated on the surface of a gold nanoparticle in the form of SNAs mediate the formation of a protein corona that is rich in complement proteins relative to SNAs composed of poly-thymine (poly-T) DNA. Cellular uptake studies show that complement receptors on macrophage cells recognize the SNA protein corona, facilitating their internalization, and causing G-rich SNAs to accumulate in the liver and spleen more than poly-T SNAs in vivo. These results support the conclusion that nucleic acid sequence and architecture can mediate nanoparticle—biomolecule interactions and alter their cellular uptake and biodistribution properties and illustrate that nucleic acid sequence is an important parameter in the design of SNA therapeutics.

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Section: Resultssupporting

confidence: 83%

The Impact of Protein Corona Formation on the Macrophage Cellular Uptake and Biodistribution of Spherical Nucleic Acids

Chinen

Guan

et al. 2017

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“…Taken together, the results indicate (1) distinct increases in cellular uptake of NPs driven by an increase in particle size; (2) a dependence on NP shape, where uptake of spherical particles was greater than that of nanostars of comparable surface area; and (3) the rates of cellular uptake increased after an initial 8-h period for larger particles, which is different from uptake kinetics previously reported for 13-nm AuNP-oligonucleotide conjugates, where the most rapid uptake occurred within the first 60 min. 40 …”

Section: Resultsmentioning

confidence: 99%

Gold Nanoparticle Size and Shape Effects on Cellular Uptake and Intracellular Distribution of siRNA Nanoconstructs

Yue¹,

Feliciano²,

et al. 2017

Bioconjugate Chem.

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Gold nanoparticles (AuNPs) show potential for transfecting target cells with small interfering RNA (siRNA), but the influence of key design parameters such as the size and shape of the particle core is incomplete. This paper describes a side-by-side comparison of the in vitro response of U87 glioblastoma cells to different formulations of siRNA-conjugated gold nanoconstructs targeting the expression of isocitrate dehydrogenase 1 (IDH1) based on 13-nm spheres, 50-nm spheres, and 40-nm stars. 50-nm spheres and 40-nm stars showed much higher uptake efficiency compared to 13-nm spheres. Confocal fluorescence microscopy showed that all three formulations were localized in the endosomes at early incubation times (2 h) but that after 24 h, 50-nm spheres and 40-nm stars were neither in endosomes nor lysosomes while 13-nm spheres remained in endosomes. Transmission electron microscopy images revealed that the 13-nm spheres were enclosed and dispersed within endocytic vesicles while 50-nm spheres and 40-nm stars were aggregated, and some of these NPs were outside of endocytic vesicles. In our comparison of nanoconstructs with different sizes and shapes, while holding siRNA surface density and nanoparticle concentration constant, we found that larger particles (50-nm spheres and 40-nm stars) showed higher potential as carriers for the delivery of siRNA.

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“…Cellular uptake of all constructs in major immune cell populations including pDCs, conventional dendritic cells (cDCs), B cells, NK cells, macrophages, and granulocytes was analyzed based on conventional surface markers by flow cytometry. Cellular uptake was quantified at 8 and 24 h time points, which were chosen because uptake was expected to have reached saturation by 8 h (based on previous SNA uptake studies using different cell lines) and internalized SNAs are predominately in endosomes . The 24 h time‐point was chosen to remain consistent with literature for comparison purposes; it is a treatment time that many labs use to evaluate immunological response …”

Section: Resultsmentioning

confidence: 99%

RNA‐Based Immunostimulatory Liposomal Spherical Nucleic Acids as Potent TLR7/8 Modulators

Guan

Chernyak

Dominguez

et al. 2018

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Immunostimulatory spherical nucleic acids (IS-LSNAs) comprised of RNA selective for toll-like receptors (TLRs) 7/8 are synthesized and characterized. These structures consist of liposomal cores functionalized with a dense shell of RNA inserted into the wall of the lipid core via hydrophobic cholesterol moieties. IS-LSNAs potently activate TLR7/8 via NF-κΒ signaling in reporter cell lines and in primary immune cells as evidenced by cytokine production and the upregulation of costimulatory receptors. Importantly, they are preferentially taken up by plasmacytoid dendritic cells, an observation that makes them potentially useful for immunotherapy. In addition, these structures contain a core that can be loaded with antigens and used to prime T cells. In this regard, it is shown that dendritic cells treated with IS-SNAs loaded with ovalbumin peptide can prime ova specific CD8+ T cells. In addition to introducing the first IS-LSNAs consisting of RNA, these experiments show that one can facilitate an antigen-specific T cell response greater than that of free or cationic lipid-transfected RNA of the same sequence selective for TLR7/8. This work points toward the promise of using IS-LSNAs comprised of RNA as potent and highly tunable TLR-specific agents for the development of vaccines and other pharmaceuticals that require selective immunomodulation.

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The Sequence‐Specific Cellular Uptake of Spherical Nucleic Acid Nanoparticle Conjugates

Cited by 65 publications

References 44 publications

The Impact of Protein Corona Formation on the Macrophage Cellular Uptake and Biodistribution of Spherical Nucleic Acids

The Impact of Protein Corona Formation on the Macrophage Cellular Uptake and Biodistribution of Spherical Nucleic Acids

Gold Nanoparticle Size and Shape Effects on Cellular Uptake and Intracellular Distribution of siRNA Nanoconstructs

RNA‐Based Immunostimulatory Liposomal Spherical Nucleic Acids as Potent TLR7/8 Modulators

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