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Toehold-Mediated Shape Transition of Nucleic Acid Nanoparticles

  • Jordan Hartung
    Jordan Hartung
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
  • Nathan McCann
    Nathan McCann
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
  • Erwin Doe
    Erwin Doe
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
    More by Erwin Doe
  • Hannah Hayth
    Hannah Hayth
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
    More by Hannah Hayth
  • Kheiria Benkato
    Kheiria Benkato
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
  • M. Brittany Johnson
    M. Brittany Johnson
    Department of Biology, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
  • Mathias Viard
    Mathias Viard
    Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, United States
    Basic Science Program, Leidos Biomedical Research Inc. National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States
  • Kirill A. Afonin*
    Kirill A. Afonin
    Department of Chemistry, University of North Carolina at Charlotte, Charlotte, North Carolina 28223, United States
    *Email: [email protected]
  • , and 
  • Emil F. Khisamutdinov*
    Emil F. Khisamutdinov
    Department of Chemistry, Ball State University, Muncie, Indiana 47306, United States
    *Email: [email protected]
Cite this: ACS Appl. Mater. Interfaces 2023, 15, 21, 25300–25312
Publication Date (Web):May 19, 2023
https://doi.org/10.1021/acsami.3c01604
Copyright © 2023 American Chemical Society

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    Abstract

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    We introduce a toehold-mediated strand displacement strategy for regulated shape-switching of nucleic acid nanoparticles (NANPs) enabling their sequential transformation from triangular to hexagonal architectures at isothermal conditions. The successful shape transitions were confirmed by electrophoretic mobility shift assays, atomic force microscopy, and dynamic light scattering. Furthermore, implementation of split fluorogenic aptamers allowed for monitoring the individual transitions in real time. Three distinct RNA aptamers─malachite green (MG), broccoli, and mango─were embedded within NANPs as reporter domains to confirm shape transitions. While MG “lights up” within the square, pentagonal, and hexagonal constructs, the broccoli is activated only upon formation of pentagon and hexagon NANPs, and mango reports only the presence of hexagons. Moreover, the designed RNA fluorogenic platform can be employed to construct a logic gate that performs an AND operation with three single-stranded RNA inputs by implementing a non-sequential polygon transformation approach. Importantly, the polygonal scaffolds displayed promising potential as drug delivery agents and biosensors. All polygons exhibited effective cellular internalization followed by specific gene silencing when decorated with fluorophores and RNAi inducers. This work offers a new perspective for the design of toehold-mediated shape-switching nanodevices to activate different light-up aptamers for the development of biosensors, logic gates, and therapeutic devices in the nucleic acid nanotechnology.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsami.3c01604.

    • Oligonucleotide sequences used in this project; sequences and 2D structures of the DNA polygons and fluorogenic RNA polygons; design principle of mango RNA aptamer reporter; comparison of specific DNA shape transformations and sequential RNA shape transformations at ambient and physiological temperatures; fluorescence analysis of the co-transcriptional product of the hexagonal NANP; fluorescence intensity changes in the presence of ssRNA inputs; DNA polygon assembly properties from various strands evaluated by agarose gel electrophoresis; RNA polygon assembly properties evaluated by agarose gel electrophoresis; sequences and 2D structures of the RNA–DNA hybrid polygons used for in vitro assays; and agarose gel electrophoresis analysis (PDF)

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    Cited By

    This article is cited by 3 publications.

    1. Laura P. Rebolledo, Weina Ke, Edward Cedrone, Jian Wang, Krishna Majithia, M. Brittany Johnson, Nikolay V. Dokholyan, Marina A. Dobrovolskaia, Kirill A. Afonin. Immunostimulation of Fibrous Nucleic Acid Nanoparticles Can be Modulated through Aptamer-Based Functional Moieties: Unveiling the Structure–Activity Relationship and Mechanistic Insights. ACS Applied Materials & Interfaces 2024, 16 (7) , 8430-8441. https://doi.org/10.1021/acsami.3c17779
    2. Ross Brumett, Leyla Danai, Abigail Coffman, Yasmine Radwan, Megan Teter, Hannah Hayth, Erwin Doe, Katelynn Pranger, Sable Thornburgh, Allison Dittmer, Zhihai Li, Tae Jin Kim, Kirill A. Afonin, Emil F. Khisamutdinov. Design and Characterization of Compact, Programmable, Multistranded Nonimmunostimulatory Nucleic Acid Nanoparticles Suitable for Biomedical Applications. Biochemistry 2024, 63 (3) , 312-325. https://doi.org/10.1021/acs.biochem.3c00615
    3. Damian Beasock, Anh Ha, Justin Halman, Martin Panigaj, Jian Wang, Nikolay V. Dokholyan, Kirill A. Afonin. Break to Build: Isothermal Assembly of Nucleic Acid Nanoparticles (NANPs) via Enzymatic Degradation. Bioconjugate Chemistry 2023, 34 (6) , 1139-1146. https://doi.org/10.1021/acs.bioconjchem.3c00167

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