Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Biocomputing based on particle disassembly

Abstract

Nanoparticles with biocomputing capabilities could potentially be used to create sophisticated robotic devices with a variety of biomedical applications, including intelligent sensors and theranostic agents. DNA/RNA-based computing techniques have already been developed that can offer a complete set of Boolean logic functions and have been used, for example, to analyse cells and deliver molecular payloads. However, the computing potential of particle-based systems remains relatively unexplored. Here, we show that almost any type of nanoparticle or microparticle can be transformed into autonomous biocomputing structures that are capable of implementing a functionally complete set of Boolean logic gates (YES, NOT, AND and OR) and binding to a target as result of a computation. The logic-gating functionality is incorporated into self-assembled particle/biomolecule interfaces (demonstrated here with proteins) and the logic gating is achieved through input-induced disassembly of the structures. To illustrate the capabilities of the approach, we show that the structures can be used for logic-gated cell targeting and advanced immunoassays.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Conceptual designs of biocomputing structures for YES/NOT/AND/OR logic basis.
Figure 2: Dependences of output on input concentration for YES gates implemented with different protein-based input-processing interfaces.
Figure 3: YES/NOT gates for CAP in different experimental set-ups.
Figure 4: Double-input gates in the set-up with 3 μm core particles, FH-HRP:STR output receptor's ligand, and quantitative peroxidase assay for output signal readout.
Figure 5: Cell targeting as the output action of logic gating.

Similar content being viewed by others

References

  1. Benenson, Y. Biomolecular computing systems: principles, progress and potential. Nature Rev. Genet. 13, 455–468 (2012).

    Article  CAS  Google Scholar 

  2. Miyamoto, T., Razavi, S., DeRose, R. & Inoue, T. Synthesizing biomolecule-based Boolean logic gates. ACS Synth. Biol. 2, 72–82 (2013).

    Article  CAS  Google Scholar 

  3. Xie, Z., Wroblewska, L., Prochazka, L., Weiss, R. & Benenson, Y. Multi-input RNAi-based logic circuit for identification of specific cancer cells. Science 333, 307–311 (2011).

    Article  Google Scholar 

  4. Katz, E. Biomolecular Information Processing: From Logic Systems to Smart Sensors and Actuators (Wiley, 2012).

    Book  Google Scholar 

  5. Adleman, L. M. Molecular computation of solutions to combinatorial problems. Science 266, 1021–1024 (1994).

    Article  CAS  Google Scholar 

  6. Mao, C., LaBean, T. H., Relf, J. H. & Seeman, N. C. Logical computation using algorithmic self-assembly of DNA triple-crossover molecules. Nature 407, 493–496 (2000).

    Article  CAS  Google Scholar 

  7. Stojanovic, M. N. & Stefanovic, D. A deoxyribozyme-based molecular automaton. Nature Biotechnol. 21, 1069–1074 (2003).

    Article  CAS  Google Scholar 

  8. Benenson, Y., Gil, B., Ben-Dor, U., Adar, R. & Shapiro, E. An autonomous molecular computer for logical control of gene expression. Nature 429, 423–429 (2004).

    Article  CAS  Google Scholar 

  9. Rothemund, P. W., Papadakis, N. & Winfree, E. Algorithmic self-assembly of DNA Sierpinski triangles. PLoS Biol. 2, e424 (2004).

    Article  Google Scholar 

  10. Seelig, G., Soloveichik, D., Zhang, D. Y. & Winfree, E. Enzyme-free nucleic acid logic circuits. Science 314, 1585–1588 (2006).

    Article  CAS  Google Scholar 

  11. Elbaz, J. et al. DNA computing circuits using libraries of DNAzyme subunits. Nature Nanotech. 5, 417–422 (2010).

    Article  CAS  Google Scholar 

  12. Pei, R., Matamoros, E., Liu, M., Stefanovic, D. & Stojanovic, M. N. Training a molecular automaton to play a game. Nature Nanotech. 5, 773–777 (2010).

    Article  CAS  Google Scholar 

  13. Qian, L. & Winfree, E. Scaling up digital circuit computation with DNA strand displacement cascades. Science 332, 1196–1201 (2011).

    Article  CAS  Google Scholar 

  14. Katz, E. & Privman, V. Enzyme-based logic systems for information processing. Chem. Soc. Rev. 39, 1835–1857 (2010).

    Article  CAS  Google Scholar 

  15. Ashkenasy, G. & Ghadiri, M. R. Boolean logic functions of a synthetic peptide network. J. Am. Chem. Soc. 126, 11140–11141 (2004).

    Article  CAS  Google Scholar 

  16. De Silva, A. P. & Uchiyama, S. Molecular logic and computing. Nature Nanotech. 2, 399–410 (2007).

    Article  CAS  Google Scholar 

  17. Liu, J. & Lu, Y. Smart nanomaterials responsive to multiple chemical stimuli with controllable cooperativity. Adv. Mater. 18, 1667–1671 (2006).

    Article  CAS  Google Scholar 

  18. Von Maltzahn, G. et al. Nanoparticle self-assembly gated by logical proteolytic triggers. J. Am. Chem. Soc. 129, 6064–6065 (2007).

    Article  CAS  Google Scholar 

  19. Frezza, B. M., Cockroft, S. L. & Ghadiri, M. R. Modular multi-level circuits from immobilized DNA-based logic gates. J. Am. Chem. Soc. 129, 14875–14879 (2007).

    Article  CAS  Google Scholar 

  20. Motornov, M. et al. ‘Chemical transformers’ from nanoparticle ensembles operated with logic. Nano Lett. 8, 2993–2997 (2008).

    Article  CAS  Google Scholar 

  21. Freeman, R., Finder, T. & Willner, I. Multiplexed analysis of Hg2+ and Ag+ ions by nucleic acid functionalized CdSe/ZnS quantum dots and their use for logic gate operations. Angew. Chem. Int. Ed. 48, 7818–7821 (2009).

    Article  CAS  Google Scholar 

  22. Angelos, S., Yang, Y. W., Khashab, N. M., Stoddart, J. F. & Zink, J. I. Dual-controlled nanoparticles exhibiting AND logic. J. Am. Chem. Soc. 131, 11344–11346 (2009).

    Article  CAS  Google Scholar 

  23. Wen, Y. et al. DNA-based intelligent logic controlled release systems. Chem. Commun. 48, 8410–8412 (2012).

    Article  CAS  Google Scholar 

  24. Huang, Z., Tao, Y., Pu, F., Ren, J. & Qu, X. Versatile logic devices based on programmable DNA-regulated silver-nanocluster signal transducers. Chemistry 18, 6663–6669 (2012).

    Article  CAS  Google Scholar 

  25. Chen, J., Fang, Z., Lie, P. & Zeng, L. Computational lateral flow biosensor for proteins and small molecules: a new class of strip logic gates. Anal Chem. 84, 6321–6325 (2012).

    Article  CAS  Google Scholar 

  26. Rudchenko, M. et al. Autonomous molecular cascades for evaluation of cell surfaces. Nature Nanotech. 8, 580–586 (2013).

    Article  CAS  Google Scholar 

  27. You, M. et al. DNA ‘Nano-claw’: logic-based autonomous cancer targeting and therapy. J. Am. Chem. Soc. 136, 1256–1259 (2014).

    Article  CAS  Google Scholar 

  28. Xie, J., Lee, S. & Chen, X. Nanoparticle-based theranostic agents. Adv. Drug Deliv. Rev. 62, 1064–1079 (2010).

    Article  CAS  Google Scholar 

  29. Douglas, S. M., Bachelet, I. & Church, G. M. A logic-gated nanorobot for targeted transport of molecular payloads. Science 17, 831–834 (2012).

    Article  Google Scholar 

  30. Rubenstein, K. E., Schneider, R. S. & Ullman, E. F. ‘Homogeneous’ enzyme immunoassay. A new immunochemical technique. Biochem. Biophys. Res. Commun. 47, 846–851 (1972).

    Article  CAS  Google Scholar 

  31. Reeves, C. M. An Introduction to Logical Designs of Digital Circuits (Cambridge Univ. Press, 1972).

    Google Scholar 

  32. Nikitin, M. P., Zdobnova, T. A., Lukash, S. V., Stremovskiy, O. A. & Deyev, S. M. Protein-assisted self-assembly of multifunctional nanoparticles. Proc. Natl Acad. Sci. USA 107, 5827–5832 (2010).

    Article  CAS  Google Scholar 

  33. Aghayeva, U. F., Nikitin, M. P., Lukash, S. V. & Deyev, S. M. Denaturation-resistant bifunctional colloidal superstructures assembled via the proteinaceous barnase–barstar interface. ACS Nano 7, 950–961 (2013).

    Article  CAS  Google Scholar 

  34. Schwertmann, U. & Cornell, R. M. in Iron Oxides in the Laboratory: Preparation and Characterization 2nd edn, 103–112 (Wiley, 2000).

    Book  Google Scholar 

  35. Nikitin, P. I. & Vetoshko, P. M. Meter of magnetic susceptibility. Russian patent no. RU2177611 (2000).

  36. Nikitin, P. I. & Vetoshko, P. M. Analysis of biological and/or chemical mixtures using magnetic particles. Russian patent no. RU2166751 (2000), European patent no. EP1262766 (2001) and European patent no. EP2120041 (2001).

  37. Orlov, A. V. et al. Magnetic immunoassay for detection of staphylococcal toxins in complex media. Anal. Chem. 85, 1154–1163 (2013).

    Article  CAS  Google Scholar 

  38. Nikitin, P. I., Vetoshko, P. M. & Ksenevich, T. I. New type of biosensors based on magnetic nanoparticle detection. J. Magn. Magn. Mater. 311, 445–449 (2007).

    Article  CAS  Google Scholar 

  39. Nikitin, M. P., Torno, M., Chen, H., Rosengart, A. & Nikitin, P. I. Quantitative real-time in vivo detection of magnetic nanoparticles by their non-linear magnetization. J. Appl. Phys. 103, 07A304 (2008).

    Article  Google Scholar 

  40. Gabor, F., Bogner, E., Weissenboeck, A. & Wirth, M. The lectin–cell interaction and its implications to intestinal lectin-mediated drug delivery. Adv. Drug Deliv. Rev. 56, 459–480 (2004).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank A.V. Orlov (General Physics Institute, RAS) and P.M. Vetoshko (Institute of Radio Engineering and Electronics, RAS) for assistance with magnetic measurements, A.V. Zherdev and B.B. Dzantiev (Institute of Biochemistry, RAS) for providing the CAP antibody, and I.E. Deyev (Institute of Bioorganic Chemistry, RAS) for supplying GST.

Author information

Authors and Affiliations

Authors

Contributions

M.P.N. conceived the idea, designed the study and performed the experiments. V.O.S. assisted with cell targeting experiments. M.P.N., S.M.D. and P.I.N. analysed data and wrote the manuscript.

Corresponding authors

Correspondence to Maxim P. Nikitin or Sergey M. Deyev.

Ethics declarations

Competing interests

Two patent applications have been filed by M.P.N. (1) Nikitin, M.P. Logic element complex based on biomolecules (variants). Russian patent no. RU2491631, PCT application WO2013151465 (2012). (2) Nikitin, M.P. Method for determining the content of a ligand in a sample (alternatives). Russian patent no. RU2517161, PCT application WO2013151464 (2012).

Supplementary information

Supplementary information

Supplementary Information (PDF 3198 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nikitin, M., Shipunova, V., Deyev, S. et al. Biocomputing based on particle disassembly. Nature Nanotech 9, 716–722 (2014). https://doi.org/10.1038/nnano.2014.156

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2014.156

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research