Digitally encoded DNA nanostructures for multiplexed, single-molecule protein sensing with nanopores
Abstract
The simultaneous detection of a large number of different analytes is important in bionanotechnology research and in diagnostic applications. Nanopore sensing is an attractive method in this regard as the approach can be integrated into small, portable device architectures, and there is significant potential for detecting multiple sub-populations in a sample. Here, we show that highly multiplexed sensing of single molecules can be achieved with solid-state nanopores by using digitally encoded DNA nanostructures. Based on the principles of DNA origami, we designed a library of DNA nanostructures in which each member contains a unique barcode; each bit in the barcode is signalled by the presence or absence of multiple DNA dumbbell hairpins. We show that a 3-bit barcode can be assigned with 94% accuracy by electrophoretically driving the DNA structures through a solid-state nanopore. Select members of the library were then functionalized to detect a single, specific antibody through antigen presentation at designed positions on the DNA. This allows us to simultaneously detect four different antibodies of the same isotype at nanomolar concentration levels.
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In nanopore reads of labeled DNA, each label is read in [10-1; 101] ms.
“Conversely, in regards to nanopore reads of labeled DNA, each label is read in [10–1; 101] ms.”
From Emerging Approaches to DNA Data Storage: Challenges and Prospects (2022) · cites this paper as [21]
Bell and Keyser used conical quartz nanopores with diameters of ∼14 nm for a 3-bit barcode that could be assigned with 94% accuracy.
“The authors used conical quartz nanopores with diameters of ∼14 nm for a 3-bit barcode that could be assigned with 94% accuracy.”
From Emerging Approaches to DNA Data Storage: Challenges and Prospects (2022) · cites this paper as [21]
Bell and Keyser fabricated DNA barcodes to capture proteins.
“The use of nanopores to read out digital information encoded in DNA nanostructures was demonstrated by Bell and Keyser, who fabricated “DNA barcodes” to capture proteins.21”
From Emerging Approaches to DNA Data Storage: Challenges and Prospects (2022) · cites this paper as [21]
Long DNA backbones as in DNA origami can organize DNA protrusions to produce three-dimensional DNA barcodes or hard drives that may be read using solid-state nanopores.
“More recently, through the use of long DNA backbones as in DNA origami, the organization of DNA protrusions has been used to produce three-dimensional DNA barcodes21 or hard drives that may be read using solid-state nanopores.”
From Emerging Approaches to DNA Data Storage: Challenges and Prospects (2022) · cites this paper as [21]
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“Still, our sys-tem could be compatible with different types of readouts including single-molecule methods such as nanopore (38), AFM (37), and centrifuge force microscope (CFM) (39).”
MethodQuipuNet: Convolutional Neural Network for Single-Molecule Nanopore Sensing
Misiunas, K., Ermann, N., & Keyser, U. F. (2018) · Nano Letters · doi:10.1021/acs.nanolett.8b01709 · Cited by 82 · see citing works
“In our demonstration, we use a previously published dataset on multiplexed single-molecule protein sensing [1].”
BackgroundMethodInfluentialSelf-citationAsymmetric dynamics of DNA entering and exiting a strongly confining nanopore
Bell, N. A. W., Chen, K., Ghosal, S., Ricci, M., & Keyser, U. F. (2017) · Nature Communications · doi:10.1038/s41467-017-00423-9 · Cited by 81 · see citing works
Self-citationDetecting topological variations of DNA at single-molecule level
Liu, K., Pan, C., Kuhn, A., Nievergelt, A. P., Fantner, G. E., Milenković, O., & Rađenović, A. (2018) · Nature Communications · doi:10.1038/s41467-018-07924-1 · Cited by 81 · see citing works
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The Utility of Nanopore Technology for Protein and Peptide Sensing
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Current Blockades of Proteins inside Nanopores for Real-Time Metabolome Analysis
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Single-Molecule Analysis with Solid-State Nanopores
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Microfluidics for Protein Biophysics
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Deep learning for single-molecule science
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“Single-molecule sensing, sequencing and characterisation based on electric or optical techniques can generate very large datasets, in some cases in a ( semi-) automated fashion [ 1 – 4 ] .”
BackgroundCritical Review: digital resolution biomolecular sensing for diagnostics and life science research
Huang, Q., Li, N., Zhang, H., Che, C., Sun, F., Xiong, Y., Canady, T. D., & Cunningham, B. T. (2020) · Lab on a Chip · doi:10.1039/d0lc00506a · Cited by 70 · see citing works
Simultaneous identification of viruses and viral variants with programmable DNA nanobait
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Self-citationMultiplexed DNA Identification Using Site Specific dCas9 Barcodes and Nanopore Sensing
Weckman, N. E., Ermann, N., Gutierrez, R., Chen, K., Graham, J. E., Tivony, R., Heron, A., & Keyser, U. F. (2019) · ACS Sensors · doi:10.1021/acssensors.9b00686 · Cited by 69 · see citing works
Self-citationSingle molecule based SNP detection using designed DNA carriers and solid-state nanopores.
Kong, J.-L., Zhu, J., & Keyser, U. (2017) · Chemical Communications · doi:10.1039/c6cc08621g · Cited by 45 · see citing works
Self-citationImage Encoding Using Multi‐Level DNA Barcodes with Nanopore Readout
Zhu, J., Ermann, N., Chen, K., & Keyser, U. F. (2021) · Small · doi:10.1002/smll.202100711 · Cited by 66 · see citing works
Self-citationLocalized detection of ions and biomolecules with a force-controlled scanning nanopore microscope
Aramesh, M., Forró, C., Dorwling‐Carter, L., Lüchtefeld, I., Schlotter, T., Ihle, S. J., Shorubalko, I., Hosseini, V., Momotenko, D., Zambelli, T., et al. (2019) · Nature Nanotechnology · doi:10.1038/s41565-019-0493-z · Cited by 66 · see citing works
Precise DNA Concentration Measurements with Nanopores by Controlled Counting
Charron, M., Briggs, K., King, S., Waugh, M. J., & Tabard‐Cossa, V. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b01900 · Cited by 65 · see citing works
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Analyte‐Triggered DNA‐Probe Release from a Triplex Molecular Beacon for Nanopore Sensing
Guo, B., Sheng, Y., Zhou, K., Liu, Q., Liu, L., & Wu, H. (2018) · Angewandte Chemie International Edition · doi:10.1002/anie.201711690 · Cited by 64 · see citing works
Nanopore electric snapshots of an RNA tertiary folding pathway
Zhang, X., Zhang, D., Zhao, C., Tian, K., Shi, R., Du, X. J., Burcke, A. J., Wang, J., Chen, S., & Gu, L. (2017) · Nature Communications · doi:10.1038/s41467-017-01588-z · Cited by 63 · see citing works
1/ f noise in solid-state nanopores is governed by access and surface regions
Fragasso, A., Pud, S., & Dekker, C. (2019) · Nanotechnology · doi:10.1088/1361-6528/ab2d35 · Cited by 63 · see citing works
“small pores within a SiN membrane, can efficiently detect the analyte molecules [15, 16], read-out certain structural features of the detected molecules [8, 17, 18], and even discriminate short nucleotide sequences [19].”
BackgroundChen, K., Juhasz, M., Gularek, F., Weinhold, E. G., Tian, Y., Keyser, U. F., & Bell, N. A. W. (2017) · Nano Letters · doi:10.1021/acs.nanolett.7b01009 · Cited by 62 · see citing works
Self-citationHybridization Biosensors Relying on Electrical Properties of Nucleic Acids
Ferapontova, E. E. (2016) · Electroanalysis · doi:10.1002/elan.201600593 · Cited by 60 · see citing works
Nanopipettes—The past and the present
Stanley, J., & Pourmand, N. (2020) · APL Materials · doi:10.1063/5.0020011 · Cited by 59 · see citing works
Nanopore Detection Using Supercharged Polypeptide Molecular Carriers
Wang, X.-Y., Thomas, T., Ren, R., Zhou, Y., Zhang, P., Li, J.-J., Cai, S., Liu, K., Ivanov, A., Herrmann, A., et al. (2023) · Journal of the American Chemical Society · doi:10.1021/jacs.2c13465 · Cited by 51 · see citing works
Comparing proteins and nucleic acids for next-generation biomolecular engineering
Pugh, G., Burns, J. R., & Howorka, S. (2018) · Nature Reviews Chemistry · doi:10.1038/s41570-018-0015-9 · Cited by 58 · see citing works
Direction- and Salt-Dependent Ionic Current Signatures for DNA Sensing with Asymmetric Nanopores
Chen, K., Bell, N. A. W., Kong, J., Tian, Y., & Keyser, U. F. (2017) · Biophysical Journal · doi:10.1016/j.bpj.2016.12.033 · Cited by 57 · see citing works
Self-citationRecent advances in integrated solid-state nanopore sensors
Rahman, M., Sampad, M. J. N., Hawkins, A. R., & Schmidt, H. (2021) · Lab on a Chip · doi:10.1039/d1lc00294e · Cited by 55 · see citing works
DNA‐Based Nanofabrication for Nanoelectronics
Hui, L., Bai, R., & Liu, H. (2022) · Advanced Functional Materials · doi:10.1002/adfm.202112331 · Cited by 55 · see citing works
Optical Voltage Sensing Using DNA Origami
Hemmig, E. A., Fitzgerald, C., Maffeo, C., Hecker, L., Ochmann, S. E., Aksimentiev, A., Tinnefeld, P., & Keyser, U. F. (2018) · Nano Letters · doi:10.1021/acs.nanolett.7b05354 · Cited by 55 · see citing works
Self-citationSolid-state and polymer nanopores for protein sensing: A review
Meyer, N., Nemeir, I. A., Janot, J., Torrent, J., Lepoitevin, M., & Balme, S. (2021) · Advances in Colloid and Interface Science · doi:10.1016/j.cis.2021.102561 · Cited by 54 · see citing works
High bandwidth approaches in nanopore and ion channel recordings - A tutorial review
Hartel, A. J. W., Shekar, S., Ong, P., Schroeder, I., Thiel, G., & Shepard, K. L. (2019) · Analytica Chimica Acta · doi:10.1016/j.aca.2019.01.034 · Cited by 53 · see citing works
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Replication‐induced DNA secondary structures drive fork uncoupling and breakage
Williams, S. L., Casas-Delucchi, C. S., Raguseo, F., Guneri, D., Li, Y., Minamino, M., Fletcher, E. E., Yeeles, J. T. P., Keyser, U. F., Waller, Z. A. E., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2023114334 · Cited by 51 · see citing works
“The linear ssDNA scaffold for our designs as the positive control and negative control was obtained by cutting circular M13mp18 DNA (New England Biolabs) at BamHI-HF and EcoRI-HF (New England Biolabs, 100 units/ μ l) restriction sites following our published protocol (Bell & Keyser, 2016).”
BackgroundMethodInfluentialSelf-citationSuper‐Resolution Detection of DNA Nanostructures Using a Nanopore
Chen, K., Choudhary, A., Sandler, S. E., Maffeo, C., Ducati, C., Aksimentiev, A., & Keyser, U. F. (2023) · Advanced Materials · doi:10.1002/adma.202207434 · Cited by 51 · see citing works
Self-citationPromoting single-file DNA translocations through nanopores using electro-osmotic flow
Ermann, N., Hanikel, N., Wang, V., Chen, K., Weckman, N. E., & Keyser, U. F. (2018) · The Journal of Chemical Physics · doi:10.1063/1.5031010 · Cited by 50 · see citing works
Self-citationSpecific Biosensing Using DNA Aptamers and Nanopores
Kong, J., Zhu, J., Chen, K., & Keyser, U. F. (2018) · Advanced Functional Materials · doi:10.1002/adfm.201807555 · Cited by 50 · see citing works
Self-citationSingle Molecule DNA Resensing Using a Two‐Pore Device
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Shot noise sets the limit of quantification in electrochemical measurements
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Single‐Molecule Binding Assay Using Nanopores and Dimeric NP Conjugates
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Promoting single-file DNA translocations through nanopores using electro-osmotic flow
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Self-citationOptical Nanopore Sensors for Quantitative Analysis
Fried, J. P., Wu, Y., Tilley, R. D., & Gooding, J. J. (2022) · Nano Letters · doi:10.1021/acs.nanolett.1c03976 · Cited by 48 · see citing works
Nanopores: a versatile tool to study protein dynamics.
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“…protein interaction has been studied using DNA carriers and solid-state nanopores: e.g. directly for dCas9 interactions [113,114], or using epitope [115] or aptamer [116] functionalized DNA constructs as designed by the Keyser and Edel labs to specifically detect antibodies, avidin, etc. Lastly,…”
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Advanced DNA Nanopore Technologies
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Label-Free, Multiplexed, Single-Molecule Analysis of Protein–DNA Complexes with Nanopores
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- Authors
- Bell, N. A. W., & Keyser, U. F.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Bell, Nicholas A. W.
- Keyser, Ulrich F.
- Venue
- Nature Nanotechnology
- Published
- 2016-04-04
- Volume
- 11
- Issue
- 7
- Pages
- 645-651
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- OpenAlex
- W2329887558
- Cited by
- 345
- References
- 45
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 24 · 2023: 38 · 2022: 39 · 2021: 30 · 2020: 34 · 2019: 39 · 2018: 40 · 2017: 25 · 2016: 10 · 2015: 1
- FWCI
- 18.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Nanotechnology (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- Funders
- Engineering and Physical Sciences Research Council
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › Nanopore and Nanochannel Transport Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Physical Sciences › Engineering › Electrical and Electronic Engineering › Electrochemical sensors and biosensors
- Keywords
- DNA nanostructures, DNA origami, solid-state nanopores, nanopore sensing, multiplexed protein detection, single-molecule detection, DNA barcodes, antibody detection, antigen presentation
- MeSH terms
- Binding Sites, DNA, Proteins, Nanotechnology, Nanostructures, Nanopores
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