Advertisement

Programmable RNA-based systems for sensing and diagnostic applications

  • Marianna Rossetti
  • Erica Del Grosso
  • Simona Ranallo
  • Davide Mariottini
  • Andrea Idili
  • Alessandro BertucciEmail author
  • Alessandro PorchettaEmail author
Trends
Part of the following topical collections:
  1. Young Investigators in (Bio-)Analytical Chemistry

Abstract

The emerging field of RNA nanotechnology harnesses the versatility of RNA molecules to generate nature-inspired systems with programmable structure and functionality. Such methodology has therefore gained appeal in the fields of biosensing and diagnostics, where specific molecular recognition and advanced input/output processing are demanded. The use of RNA modules and components allows for achieving diversity in structure and function, for processing information with molecular precision, and for programming dynamic operations on the grounds of predictable non-covalent interactions. When RNA nanotechnology meets bioanalytical chemistry, sensing of target molecules can be performed by harnessing programmable interactions of RNA modules, advanced field-ready biosensors can be manufactured by interfacing RNA-based devices with supporting portable platforms, and RNA sensors can be engineered to be genetically encoded allowing for real-time imaging of biomolecules in living cells. In this article, we report recent advances in RNA-based sensing technologies and discuss current trends in RNA nanotechnology-enabled biomedical diagnostics. In particular, we describe programmable sensors that leverage modular designs comprising dynamic aptamer-based units, synthetic RNA nanodevices able to perform target-responsive regulation of gene expression, and paper-based sensors incorporating artificial RNA networks.

Graphical Abstract

Keywords

RNA aptamers Diagnostics Synthetic biology Toehold switches RNA nanotechnology 

Notes

Funding information

A.P. received support from the University of Rome Tor Vergata under the grant “MIRA” no E81I18000200005. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement no 704120 (“MIRNANO”). A.B. is a global Marie Skłodowska-Curie fellow. M.R. and S.R. are supported from a Fondazione Umberto Veronesi “postdoctoral fellowship 2019”. 

Compliance with ethical standards

No experiments involving human participants and/or animals have been conducted for this publication.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Engelhart AE. RNA imaging: a tale of two G-quadruplexes. Nat Chem Biol. 2017;13(11):1140–1.CrossRefGoogle Scholar
  2. 2.
    Guo P. The emerging field of RNA nanotechnology. Nat Nanotechnol. 2010;5(12):833–42.CrossRefGoogle Scholar
  3. 3.
    Grabow WW, Jaeger L. RNA self-assembly and RNA nanotechnology. Acc Chem Res. 2014;47(6):1871–80.CrossRefGoogle Scholar
  4. 4.
    Jasinski D, Haque F, Binzel DW, Guo P. Advancement of the emerging field of RNA nanotechnology. ACS Nano. 2017;11(2):1142–64.CrossRefGoogle Scholar
  5. 5.
    Chappell J, Watters KE, Takahashi MK, Lucks JB. A renaissance in RNA synthetic biology: new mechanisms, applications and tools for the future. Curr Opin Chem Biol. 2015;28:47–56.CrossRefGoogle Scholar
  6. 6.
    Slomovic S, Pardee K, Collins JJ. Synthetic biology devices for in vitro and in vivo diagnostics. Proc Natl Acad Sci U S A. 2015;112(47):14429–35.CrossRefGoogle Scholar
  7. 7.
    Bailey RC. Grand Challenge Commentary: Informative diagnostics for personalized medicine. Nat Chem Biol. 2010;6(12):857–9.CrossRefGoogle Scholar
  8. 8.
    Bouhedda F, Autour A, Ryckelynck M. Light-up RNA aptamers and their cognate fluorogens: from their development to their applications. Int J Mol Sci. 2018;19(1):E44.CrossRefGoogle Scholar
  9. 9.
    Neubacher S, Hennig S. RNA structure and cellular applications of fluorescent light-up aptamers. Angew Chem Int Ed. 2018.  https://doi.org/10.1002/anie.201806482.
  10. 10.
    Ouellet J. RNA Fluorescence with light-up aptamers. Front Chem. 2016;4:29.CrossRefGoogle Scholar
  11. 11.
    Szeto K, Latulippe DR, Ozer A, Pagano JM, White BS, Shalloway D, et al. RAPID-SELEX for RNA aptamers. PLoS One. 2013;8(12):e82667.CrossRefGoogle Scholar
  12. 12.
    Gotrik M, Sekhon G, Saurabh S, Nakamoto M, Eisenstein M, Soh HT. Direct selection of fluorescence-enhancing RNA aptamers. J Am Chem Soc. 2018;140(10):3583–91.CrossRefGoogle Scholar
  13. 13.
    Xu W, Lu Y. Label-free fluorescent aptamer sensor based on regulation of malachite green fluorescence. Anal Chem. 2010;82(2):574–8.CrossRefGoogle Scholar
  14. 14.
    Bang GS, Cho S, Lee N, Lee B-R, Kim J-H, Kim B-G. Rational design of modular allosteric aptamer sensor for label-free protein detection. Biosens Bioelectron. 2013;39(1):44–50.CrossRefGoogle Scholar
  15. 15.
    Paige JS, Wu KY, Jaffrey SR. RNA mimics of green fluorescent protein. Science. 2011;333(6042):642–6.CrossRefGoogle Scholar
  16. 16.
    Filonov GS, Moon JD, Svensen N, Jaffrey SR. Broccoli: rapid selection of an RNA mimic of green fluorescent protein by fluorescence-based selection and directed evolution. J Am Chem Soc. 2014;136(46):16299–308.CrossRefGoogle Scholar
  17. 17.
    Dolgosheina EV, Jeng SCY, Panchapakesan SSS, Cojocaru R, Chen PSK, Wilson PD, et al. RNA Mango aptamer-fluorophore: a bright, high-affinity complex for RNA labeling and tracking. ACS Chem Biol. 2014;9(10):2412–20.CrossRefGoogle Scholar
  18. 18.
    You M, Litke JL, Jaffrey SR. Imaging metabolite dynamics in living cells using a Spinach-based riboswitch. Proc Natl Acad Sci. 2015;112(21):E2756.CrossRefGoogle Scholar
  19. 19.
    Ying Z-M, Wu Z, Tu B, Tan W, Jiang J-H. Genetically encoded fluorescent RNA sensor for ratiometric imaging of microRNA in living tumor cells. J Am Chem Soc. 2017;139(29):9779–82.CrossRefGoogle Scholar
  20. 20.
    Jepsen MDE, Sparvath SM, Nielsen TB, Langvad AH, Grossi G, Gothelf KV, et al. Development of a genetically encodable FRET system using fluorescent RNA aptamers. Nat Commun. 2018;9(1):18.CrossRefGoogle Scholar
  21. 21.
    Warner KD, Chen MC, Song W, Strack RL, Thorn A, Jaffrey SR, et al. Structural basis for activity of highly efficient RNA mimics of green fluorescent protein. Nat Struct Mol Biol. 2014;21(8):658–63.CrossRefGoogle Scholar
  22. 22.
    Paige JS, Nguyen-Duc T, Song W, Jaffrey SR. Fluorescence imaging of cellular metabolites with RNA. Science. 2012;335(6073):1194.CrossRefGoogle Scholar
  23. 23.
    Park MH, Igarashi K. Polyamines and their metabolites as diagnostic markers of human diseases. Biomol Ther. 2013;21(1):1–9.CrossRefGoogle Scholar
  24. 24.
    Fernie AR, Trethewey RN, Krotzky AJ, Willmitzer L. Metabolite profiling: from diagnostics to systems biology. Nat Rev Mol Cell Biol. 2004;5(9):763–9.CrossRefGoogle Scholar
  25. 25.
    Aw SS, Tang MX, Teo YN, Cohen SM. A conformation-induced fluorescence method for microRNA detection. Nucleic Acids Res. 2016;44(10):e92.CrossRefGoogle Scholar
  26. 26.
    Huang K, Doyle F, Wurz ZE, Tenenbaum SA, Hammond RK, Caplan JL, et al. FASTmiR: an RNA-based sensor for in vitro quantification and live-cell localization of small RNAs. Nucleic Acids Res. 2017;45(14):e130.CrossRefGoogle Scholar
  27. 27.
    Krichevsky AM, Gabriely G. miR-21: a small multi-faceted RNA. J Cell Mol Med. 2008;13(1):39–53.CrossRefGoogle Scholar
  28. 28.
    Autour A, Jeng SCY, Cawte DA, Abdolahzadeh A, Galli A, Panchapakesan SSS, et al. Fluorogenic RNA Mango aptamers for imaging small non-coding RNAs in mammalian cells. Nat Commun. 2018;9(1):656.CrossRefGoogle Scholar
  29. 29.
    Wang Z, Luo Y, Xie X, Hu X, Song H, Zhao Y, et al. In situ spatial complementation of aptamer-mediated recognition enables live-cell imaging of native RNA transcripts in real time. Angew Chem Int Ed. 2018;57(4):972–6.CrossRefGoogle Scholar
  30. 30.
    Bertucci A, Porchetta A, Ricci F. Antibody-templated assembly of an RNA mimic of green fluorescent protein. Anal Chem. 2018;90(2):1049–53.CrossRefGoogle Scholar
  31. 31.
    Karunanayake Mudiyanselage APKK, Yu Q, Leon-Duque MA, Zhao B, Wu R, You M. Genetically encoded catalytic hairpin assembly for sensitive RNA imaging in live cells. J Am Chem Soc. 2018;140(28):8739–45.CrossRefGoogle Scholar
  32. 32.
    Michnick SW, Ear PH, Manderson EN, Remy I, Stefan E. Universal strategies in research and drug discovery based on protein-fragment complementation assays. Nat Rev Drug Discov. 2007;6(7):569–82.CrossRefGoogle Scholar
  33. 33.
    Zhang H, Li F, Dever B, Wang C, Li X-F, Le XC. Assembling DNA through affinity binding to achieve ultrasensitive protein detection. Angew Chem Int Ed. 2013;52(41):10698–705.CrossRefGoogle Scholar
  34. 34.
    Kolpashchikov DM. Binary malachite green aptamer for fluorescent detection of nucleic acids. J Am Chem Soc. 2005;127(36):12442–3.CrossRefGoogle Scholar
  35. 35.
    Kikuchi N, Kolpashchikov DM. Split Spinach aptamer for highly selective recognition of DNA and RNA at ambient temperatures. Chembiochem. 2016;17(17):1589–92.CrossRefGoogle Scholar
  36. 36.
    Kikuchi N, Kolpashchikov DM. A universal split spinach aptamer (USSA) for nucleic acid analysis and DNA computation. Chem Commun. 2017;53(36):4977–80.CrossRefGoogle Scholar
  37. 37.
    Rogers TA, Andrews GE, Jaeger L, Grabow WW. Fluorescent monitoring of RNA assembly and processing using the split-Spinach aptamer. ACS Synth Biol. 2015;4(2):162–6.CrossRefGoogle Scholar
  38. 38.
    Alam KK, Tawiah KD, Lichte MF, Porciani D, Burke DH. A fluorescent split aptamer for visualizing RNA-RNA assembly in vivo. ACS Synth Biol. 2017;6(9):1710–21.CrossRefGoogle Scholar
  39. 39.
    Xie M, Fussenegger M. Designing cell function: assembly of synthetic gene circuits for cell biology applications. Nat Rev Mol Cell Biol. 2018;19(8):507–25.CrossRefGoogle Scholar
  40. 40.
    Masubuchi T, Endo M, Iizuka R, Iguchi A, Yoon DH, Sekiguchi T, et al. Construction of integrated gene logic-chip. Nat Nanotechnol. 2018;13(10):933–40.CrossRefGoogle Scholar
  41. 41.
    Nielsen AAK, Der BS, Shin J, Vaidyanathan P, Paralanov V, Strychalski EA, et al. Genetic circuit design automation. Science. 2016;352(6281):7341.CrossRefGoogle Scholar
  42. 42.
    McKeague M, Wong RS, Smolke CD. Opportunities in the design and application of RNA for gene expression control. Nucleic Acids Res. 2016;44(7):2987–99.CrossRefGoogle Scholar
  43. 43.
    Etzel M, Mörl M. Synthetic riboswitches: from plug and pray toward plug and play. Biochemistry. 2017;56(9):1181–98.CrossRefGoogle Scholar
  44. 44.
    Chen YY, Jensen MC, Smolke CD. Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems. Proc Natl Acad Sci U S A. 2010;107(19):8531–6.CrossRefGoogle Scholar
  45. 45.
    Isaacs FJ, Dwyer DJ, Ding C, Pervouchine DD, Cantor CR, Collins JJ. Engineered riboregulators enable post-transcriptional control of gene expression. Nat Biotechnol. 2004;22(7):841–7.CrossRefGoogle Scholar
  46. 46.
    Bayer TS, Smolke CD. Programmable ligand-controlled riboregulators of eukaryotic gene expression. Nat Biotechnol. 2005;23(3):337–43.CrossRefGoogle Scholar
  47. 47.
    Mutalik VK, Qi L, Guimaraes JC, Lucks JB, Arkin AP. Rationally designed families of orthogonal RNA regulators of translation. Nat Chem Biol. 2012;8(5):447–54.CrossRefGoogle Scholar
  48. 48.
    Liu CC, Qi L, Lucks JB, Segall-Shapiro TH, Wang D, Mutalik VK, et al. An adaptor from translational to transcriptional control enables predictable assembly of complex regulation. Nat Methods. 2012;9(11):1088–94.CrossRefGoogle Scholar
  49. 49.
    Isaacs FJ. Synthetic biology: automated design of RNA devices. Nat Chem Biol. 2012;8(5):413–5.CrossRefGoogle Scholar
  50. 50.
    Green AA, Silver PA, Collins JJ, Yin P. Toehold switches: de-novo-designed regulators of gene expression. Cell. 2014;159(4):925–39.CrossRefGoogle Scholar
  51. 51.
    Karig DK. Cell-free synthetic biology for environmental sensing and remediation. Curr Opin Biotechnol. 2017;45:69–75.CrossRefGoogle Scholar
  52. 52.
    Parolo C, Merkoçi A. Paper-based nanobiosensors for diagnostics. Chem Soc Rev. 2013;42:450–7.CrossRefGoogle Scholar
  53. 53.
    Yamada K, Shibata H, Suzuki K, Citterio D. Toward practical application of paper-based microfluidics for medical diagnostics: state-of-the-art and challenges. Lab Chip. 2017;17:1206–49.CrossRefGoogle Scholar
  54. 54.
    Pardee K, Green AA, Ferrante T, Cameron DE, Daleykeyser A, Yin P, et al. Paper-based synthetic gene networks. Cell. 2014;159(4):940–54.CrossRefGoogle Scholar
  55. 55.
    Takahashi MK, Tan X, Dy AJ, Braff D, Akana RT, Furuta Y, et al. A low-cost paper-based synthetic biology platform for analyzing gut microbiota and host biomarkers. Nat Commun. 2018;9:3347.CrossRefGoogle Scholar
  56. 56.
    Pardee K, Green AA, Takahashi MK, Braff D, Lambert G, Lee JW, et al. Rapid, low-cost detection of Zika virus using programmable biomolecular components. Cell. 2016;165(5):1255–66.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemical Sciences and TechnologiesUniversity of Rome Tor VergataRomeItaly
  2. 2.Department of Chemistry and BiochemistryUniversity of California Santa BarbaraSanta BarbaraUSA
  3. 3.Department of Chemistry and BiochemistryUniversity of California San DiegoLa JollaUSA

Personalised recommendations