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RNA versatility, flexibility, and thermostability for practice in RNA nanotechnology and biomedical applications

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In recent years, RNA has attracted widespread attention as a unique biomaterial with distinct biophysical properties for designing sophisticated architectures in the nanometer scale. RNA is much more versatile in structure and function with higher thermodynamic stability compared to its nucleic acid counterpart DNA. Larger RNA molecules can be viewed as a modular structure built from a combination of many ‘Lego’ building blocks connected via different linker sequences. By exploiting the diversity of RNA motifs and flexibility of structure, varieties of RNA architectures can be fabricated with precise control of shape, size, and stoichiometry. Many structural motifs have been discovered and characterized over the years and the crystal structures of many of these motifs are available for nanoparticle construction. For example, using the flexibility and versatility of RNA structure, RNA triangles, squares, pentagons, and hexagons can be constructed from phi29 pRNA three‐way‐junction (3WJ) building block. This review will focus on 2D RNA triangles, squares, and hexamers; 3D and 4D structures built from basic RNA building blocks; and their prospective applications in vivo as imaging or therapeutic agents via specific delivery and targeting. Methods for intracellular cloning and expression of RNA molecules and the in vivo assembly of RNA nanoparticles will also be reviewed.

Functional assays of fusion RNA complexes harboring multiple functionalities expressed in vivo. (a) Construction of RNA complex harboring Malachite Green (MG) binding and Spinach aptamer. (b) Eight percent native PAGE verifying the fluorogenic properties of the two RNA aptamers. (c) Fluorescence spectra of MG aptamer (top) and Spinach aptamer (bottom) in solution. (Reprinted with permission from Ref . Copyright 2013 Oxford University Press)
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Application of multifunctional RNA nanoparticles in cancer research. (a) pRNA‐X nanoparticle labeled with Alexa647 distributed to retinal cells after subconjunctival injection. (Reprinted with permission from Ref . Copyright 2014 Springer International Publishing Group). (b) Folate directed delivery of 3WJ‐BRCAA1 siRNA to gastric cancers. Tumor inhibition observed in a gastric cancer xenograft mice model after systemic injection. (Reprinted with permission from Ref . Copyright 2014 Macmillan Publishers Limited). (c) Her2 aptamer directed delivery of MED siRNA to breast cancers and effect in overcoming the tamoxifen resistance of xenograft human breast cancer. (Reprinted with permission from Ref . Copyright 2016 American Chemical Society). (d) Folate directed delivery of 3WJ‐luciferase siRNA to glioblastoma and effect in silencing luciferase gene expression in glioblastoma mice model after systemic injection. (Reprinted with permission from Ref . Copyright 2015 Impact Journals, LLC). (e) EGFR aptamer directed delivery of 3WJ‐anti‐miR21 to breast cancer cells and effect in inhibition of cancer growth in orthotopic mice model after systemic injection. (Reprinted with permission from Ref . Copyright 2015 American Chemical Society). (f) PSMA aptamer directed delivery of 3WJ‐anti‐miR21 and 3WJ‐anti‐miR17 to prostate cancer cells and effect in inhibition of cancer growth in mice model after systemic injection. (Reprinted with permission from Ref . Copyright 2016 The American Society of Gene and Cell Therapy). (g) RNA‐CpG polygons induced strong cytokine induction in vivo. (Reprinted with permission from Ref . Copyright 2014 Oxford University Press). (h) Annexin A2 aptamer directed delivery of 3WJ‐doxorubicin to ovarian cancer cells, and its effect in targeting to ovarian cancer in mice model after systemic injection. (Reprinted with permission from Ref . Copyright 2017 Elsevier Inc.)
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Design and construction of RNA triangle, square, and pentagon from pRNA‐3WJ motif. (a) 3D model and atomic force microscopy (AFM) images and (b) dynamic light scattering (DLS) assay showing the size of RNA nanoparticles. (Reprinted with permission from Ref . Copyright 2014 Oxford University Press)
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Design and construction of various 3D RNA nanostructures. (a) RNA tetrahedron designed and formed by placing pRNA‐3WJ at the four corners as shown by atomic force microscopy (AFM) and cryo‐EM. (Reprinted with permission from Ref . Copyright 2016 Wiley VCH Verlag GmbH and Co. KGaA, Weinheim). (b) RNA prism designed and formed by placing pRNA‐3WJ at the six corners. Small RNA molecules, such as MG aptamer can be encapsulated inside the prism. (Reprinted with permission from Ref . Copyright 2016 Wiley VCH Verlag GmbH and Co. KGaA, Weinheim). (c, d) RNA triangular nanoprism I and tetragonal nanoprism II designed and self‐assembled by reengineered pRNA. (Reprinted with permission from Ref . Copyright 2014 Macmillan Publishers Limited). (e) Polyhedron made of tRNA subunits. (Reprinted with permission from Ref . Copyright 2010 Macmillan Publishers Limited). (f) Ten‐stranded RNA cube with dangling ends. (Reprinted with permission from Ref . Copyright 2010 Macmillan Publishers Limited). (g) Homo‐octameric prism designed and formed with a RNA tile with T junction structure. (Reprinted with permission from Ref . Copyright 2015 Macmillan Publishers Limited). (h, i) RNA dendrimer G3 and G4 designed and formed by placing pRNA‐square at the central and extended with multiple pRNA‐3WJ structures. (Reprinted with permission from Ref . Copyright 2015 Elsevier Inc.)
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Design and construction of various RNA hexamer nanostructures. (a) pRNA hexamers designed and formed through intermolecular hand‐in‐hand interactions among six pieces of pRNAs. (Reprinted with permission from Ref . Copyright 2013 RNA Society). (b) RNA hexagonal nanoring designed and formed through RNAI/II kissing complexes. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society). (c) RNA hexamers designed and formed through linking six triangles formed from pRNA‐3WJ with helixes, constructing a supramolecular pattern resembling honeycombs. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society)
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Design and construction of various RNA triangular nanostructures. (a) RNA nanotriangle designed and formed from four RNA oligos with pRNA‐3WJ motifs at the corners. (Reprinted with permission from Ref . Copyright 2014 Oxford University Press). (b) RNA nanotriangles designed and formed from two RNA oligos with two k‐turn units at each corner (PDB: 4SC1). (Reprinted with permission from Ref . Copyright 2016 The Royal Society of Chemistry). (c) RNA–protein complex nanotriangle designed and formed utilizing the interaction of k‐turn motif and L7Ae protein. (Reprinted with permission from Ref . Copyright 2011 Nature Publishing Group). (d) RNA nanotriangles designed and formed from four RNA oligos with either short or long IIa motif (PDB: 4P97, 4PHY). (Reprinted with permission from Ref . Copyright 2016 John Wiley & Sons, Inc.). (e) RNA nanotriangle designed from three tetra‐Us as building unit at the corner. (Reprinted with permission from Ref . Copyright 2017 Elsevier Inc.). (f) RNA nanotriangle designed and formed from four RNA oligos with 3WJ motifs (PDB: 11,836) at the corners. (Reprinted with permission from Ref . Copyright 2011 American Chemical Society). (g) RNA triangles designed using loop–loop interactions. Three pRNA monomers A–b′, B–e′, and E–a′ form interlocking loops to form the triangle. (Reprinted with permission from Ref . Copyright 2004 American Chemical Society)
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Design and construction of various RNA square nanostructures. (a) RNA nanosquare designed and formed from five RNA oligos with pRNA‐3WJ motifs at the corners. (Reprinted with permission from Ref . Copyright 2014 American Chemical Society). (b) RNA nanosquares designed and formed from two RNA oligos with two k‐turn units at each corner (PDB: 4SC1). (Reprinted with permission from Ref . Copyright 2016 The Royal Society of Chemistry). (c) RNA nanosquares designed from three‐way junction (3WJ) formed by tetra‐Us and helixes as building unit at the corner. (Reprinted with permission from Ref . Copyright 2017 Elsevier Inc.). (d) RNA nanosquares designed and formed from five RNA oligos with 3WJ motifs at each corner (PDB: 2OGM). (Reprinted with permission from Ref . Copyright 2016 Elsevier). (e) Tectosquare nanoparticles designed and formed from RA, 3WJ, and tRNA motifs. (Reprinted with permission from Ref . Copyright 2009 American Chemical Society). (f) RNA nanosquare designed and formed from four piece of identical RNA oligos with IIa‐1 motifs (PDB: 3P59) at the corners. (Reprinted with permission from Ref . Copyright 2011 National Academy of Sciences)
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease
RNA Structure and Dynamics > RNA Structure, Dynamics and Chemistry

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