RNA as a stable polymer to build controllable and defined nanostructures for material and biomedical applications

Abstract

The value of polymers is manifested in their vital use as building blocks in material and life sciences. Ribonucleic acid (RNA) is a polynucleic acid, but its polymeric nature in materials and technological applications is often overlooked due to an impression that RNA is seemingly unstable. Recent findings that certain modifications can make RNA resistant to RNase degradation while retaining its authentic folding property and biological function, and the discovery of ultra-thermostable RNA motifs have adequately addressed the concerns of RNA unstability. RNA can serve as a unique polymeric material to build varieties of nanostructures including nanoparticles, polygons, arrays, bundles, membrane, and microsponges that have potential applications in biomedical and material sciences. Since 2005, more than a thousand publications on RNA nanostructures have been published in diverse fields, indicating a remarkable increase of interest in the emerging field of RNA nanotechnology. In this review, we aim to: delineate the physical and chemical properties of polymers that can be applied to RNA; introduce the unique properties of RNA as a polymer; review the current methods for the construction of RNA nanostructures; describe its applications in material, biomedical and computer sciences; and, discuss the challenges and future prospects in this field.

Keywords: Biopolymer; RNA nanostructure; RNA nanotechnology; RNA therapeutics; pRNA; phi29 DNA packaging motor.

Figure 1

Design and construction of RNA nanostructures. (A) Phi 29 DNA packaging motor pRNA hexamer [110]. Reprinted with permission from Ref. [110]. Copyright 1998 Elsevier. (B) pRNA dimer and trimer [106]. Adapted with permission from Ref. [106]. Copyright 2003 American Scientific Publishers. (C) pRNA arrays [112]. Reprinted with permission from Ref. [112]. Copyright 2004 American Chemical Society. (D) RNA tecto squares [116]. Reprinted with permission from Ref. [104]. Copyright 2004 The American Association for the Advancement of Science. (E) The RNA nanoring [114]. Reprinted with permission from Ref. [114]. Copyright 2007 American Chemical Society. (F) The tRNA-based polyhedron [118]. Reprinted with permission from Ref. [118]. Copyright 2010 Nature Publishing Group. (G) Cubic RNA-based scaffolds designed in silico [144]. Reprinted with permission from Ref. [144]. Copyright 2010 Nature Publishing Group. (H) Triangular RNA—protein complex [127]. Reprinted with permission from Ref. [127]. Copyright 2011 Nature Publishing Group. (I) The self-assembling RNA square [93]. Reprinted with permission from Ref. [93]. Copyright 2011 The National Academy of Sciences of the United States of America. (J) RNA microsponges for siRNA delivery [147]. Reprinted with permission from Ref. [147]. Copyright 2012 Nature Publishing Group. (K) pRNA nanoparticles fabricated via hand-in-hand and foot-to-foot tool kits [113]. Reprinted with permission from Ref. [113]. Copyright 2013 RNA Society. (L) pRNA nanoparticles fabricated via branch extension tool kit [113]. Reprinted with permission from Ref. [113]. Copyright 2013 RNA Society. (M) Single stranded RNA origami [136]. Reprinted with permission from Ref. [136]. Copyright 2014 The American Association for the Advancement of Science. (N) Boiling-resistant RNA triangles and the array based on RNA triangles [36]. Reprinted with permission from Ref. [36]. Copyright 2014 American Chemical Society. (O) The self-assembled RNA membrane [152]. Reprinted with permission from Ref. [152]. Copyright 2014 Nature Publishing Group. (P) RNA origami tile and tube [139]. Reprinted with permission from Ref. [139]. Copyright 2014 John Wiley and Sons.

Figure 2

Construction and functional assays of thermodynamically stable pRNA-(three-way junction) 3WJ or pRNA-X nanoparticles. (A and B) HBV ribozyme assay and MG aptamer assay of pRNA-3WJ nanoparticles [123]. Adapted with permission from Ref. [123]. Copyright 2011 Nature Publishing Group. (C) Survivin gene knock-down assay of pRNA-X nanoparticles [73]. Reprinted with permission from Ref. [73]. Copyright 2012 Elsevier.

Figure 3

Construction of RNA polygons based on pRNA-3WJ. (A) Construction of RNA triangle, square and pentagon by tuning the interior pRNA-3WJ angle [92]. Reprinted with permission from Ref. [92]. Copyright 2014 Oxford University Press. (B) Construction of RNA squares with tunable sizes [125]. Reprinted with permission from Ref. [125]. Copyright 2014 American Chemical Society.

Figure 4

pRNA nanoparticles for cancer targeting. (A) pRNA-3WJ nanoparticles target folate-receptor positive tumor xenografts [123]. Reprinted with permission from Ref. [123]. Copyright 2011 Nature Publishing Group. (B) pRNA-3WJ nanoparticles target glioma [164]. Reprinted with permission from Ref. [164]. Copyright 2015 Impact Journals, LLC. (C) pRNA-X nanoparticles target folate-receptor positive tumor xenografts [73]. Reprinted with permission from Ref. [73]. Copyright 2012 Elsevier. (D) pRNA nanoparticles targeting colorectal cancer metastases [165]. Reprinted with permission from Ref. [165]. Copyright 2015 American Chemical Society.

Figure 5

Functional RNA nanostructures for therapeutics delivery and medical detection. (A) Triggered siRNA delivery based on RNA/DNA hybrid nanostructures [140]. Reprinted with permission from Ref. [140]. Copyright 2013 Nature Publishing Group. (B) QD-aptamer-doxorubicin conjugate nanoparticles as a cancer-targeted imaging, sensing and treatment platform [210]. Reprinted with permission from Ref. [210]. Copyright 2007 American Chemical Society. (C) PSMA aptamer-conjugated gold nanoparticles for targeted molecular CT imaging and therapy of prostate cancer [213]. Reprinted with permission from Ref. [213]. Copyright 2010 American Chemical Society. (D) Spherical nucleic acids scaffold for loading RNA therapeutics [191]. Reprinted with permission from Ref. [191]. Copyright 2014 American Chemical Society.

Figure 6

Spinach RNA aptamer for intracellular imaging and sensing. (A) Live-cell imaging of Spinach-tagged 5S RNA[214]. Reprinted with permission from Ref. [214]. Copyright 2011 The American Association for the Advancement of Science. (B) Imaging cellular metabolites in E. coli with sensor RNA[215]. The sensor RNA comprises Spinach (black), a transducer (orange), and a target-binding aptamer (blue). Reprinted with permission from Ref. [215]. Copyright 2012 The American Association for the Advancement of Science.

Figure 7

The basic constitution of RNA-based biosensor.

Figure 8

Advantages of RNA-based biocomputation