Skip to main content

Thank you for visiting 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.

Single-molecule nucleic acid interactions monitored on a label-free microcavity biosensor platform



Biosensing relies on the detection of molecules and their specific interactions. It is therefore highly desirable to develop transducers exhibiting ultimate detection limits. Microcavities are an exemplary candidate technology for demonstrating such a capability in the optical domain and in a label-free fashion. Additional sensitivity gains, achievable by exploiting plasmon resonances, promise biosensing down to the single-molecule level. Here, we introduce a biosensing platform using optical microcavity-based sensors that exhibits single-molecule sensitivity and is selective to specific single binding events. Whispering gallery modes in glass microspheres are used to leverage plasmonic enhancements in gold nanorods for the specific detection of nucleic acid hybridization, down to single 8-mer oligonucleotides. Detection of single intercalating small molecules confirms the observation of single-molecule hybridization. Matched and mismatched strands are discriminated by their interaction kinetics. Our platform allows us to monitor specific molecular interactions transiently, hence mitigating the need for high binding affinity and avoiding permanent binding of target molecules to the receptors. Sensor lifetime is therefore increased, allowing interaction kinetics to be statistically analysed.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Experimental set-up of whispering-gallery-mode sensing platform.
Figure 2: Detection of nanorods in the transient and binding regimes.
Figure 3: Transient nucleic acid interactions monitored with transverse electric and transverse magnetic whispering gallery modes simultaneously.
Figure 4: Discrimination of fully complementary and single-base-mismatched DNA strands by monitoring interaction kinetics for different sodium concentrations.
Figure 5: Detection of short oligonucleotides and small intercalating molecules.


  1. 1

    Vollmer, F. & Yang, L. Label-free detection with high-Q microcavities: a review of biosensing mechanisms for integrated devices. Nanophotonics 1, 267–291 (2012).

    CAS  Article  Google Scholar 

  2. 2

    Washburn, A. L., Gunn, L. C. & Bailey, R. C. Label-free quantitation of a cancer biomarker in complex media using silicon photonic microring resonators. Anal. Chem. 81, 9499–9506 (2009).

    CAS  Article  Google Scholar 

  3. 3

    Robinson, J. T., Chen, L. & Lipson, M. On-chip gas detection in silicon optical microcavities. Opt. Express 16, 4296–4301 (2008).

    CAS  Article  Google Scholar 

  4. 4

    Bahl, G. et al. Brillouin cavity optomechanics with microfluidic devices. Nature Commun. 4, 1994 (2013).

    Article  Google Scholar 

  5. 5

    Armani, A. M. & Vahala, K. J. Heavy water detection using ultra-high-Q microcavities. Opt. Lett. 31, 1896–1898 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Vollmer, F. & Arnold, S. Whispering-gallery-mode biosensing: label-free detection down to single molecules. Nature Methods 5, 591–596 (2008).

    CAS  Article  Google Scholar 

  7. 7

    Lu, T. et al. High sensitivity nanoparticle detection using optical microcavities. Proc. Natl Acad. Sci. USA 108, 5976–5979 (2011).

    CAS  Article  Google Scholar 

  8. 8

    Vollmer, F., Arnold, S. & Keng, D. Single virus detection from the reactive shift of a whispering-gallery mode. Proc. Natl Acad. Sci. USA 105, 20701–20704 (2008).

    CAS  Article  Google Scholar 

  9. 9

    Shao, L. et al. Detection of single nanoparticles and lentiviruses using microcavity resonance broadening. Adv. Mater. 25, 5616–5620 (2013).

    CAS  Article  Google Scholar 

  10. 10

    Zhu, J. G. et al. On-chip single nanoparticle detection and sizing by mode splitting in an ultrahigh-Q microresonator. Nature Photon. 4, 46–49 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Lin, S. Y., Schonbrun, E. & Crozier, K. Optical manipulation with planar silicon microring resonators. Nano Lett. 10, 2408–2411 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Mandal, S., Serey, X. & Erickson, D. Nanomanipulation using silicon photonic crystal resonators. Nano Lett. 10, 99–104 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Santiago-Cordoba, M. A., Boriskina, S. V., Vollmer, F. & Demirel, M. C. Nanoparticle-based protein detection by optical shift of a resonant microcavity. Appl. Phys. Lett. 99, 073701 (2011).

    Article  Google Scholar 

  14. 14

    Swaim, J. D., Knittel, J. & Bowen, W. P. Detection limits in whispering gallery biosensors with plasmonic enhancement. Appl. Phys. Lett. 99, 243109 (2011).

    Article  Google Scholar 

  15. 15

    Foreman, M. R. & Vollmer, F. Theory of resonance shifts of whispering gallery modes by arbitrary plasmonic nanoparticles. New J. Phys. 15, 083006 (2013).

    Article  Google Scholar 

  16. 16

    Dantham, V. R. et al. Label-free detection of single protein using a nanoplasmonic–photonic hybrid microcavity. Nano Lett. 13, 3347–3351 (2013).

    CAS  Article  Google Scholar 

  17. 17

    Santiago-Cordoba, M. A., Cetinkaya, M., Boriskina, S. V., Vollmer, F. & Demirel, M. C. Ultrasensitive detection of a protein by optical trapping in a photonic–plasmonic microcavity. J. Biophoton. 5, 629–638 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Cooper, M. A. Optical biosensors in drug discovery. Nature Rev. Drug Discov. 1, 515–528 (2002).

    CAS  Article  Google Scholar 

  19. 19

    Fan, X. D. et al. Sensitive optical biosensors for unlabeled targets: a review. Anal. Chim. Acta 620, 8–26 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Sassolas, A., Leca-Bouvier, B. D. & Blum, L. J. DNA biosensors and microarrays. Chem. Rev. 108, 109–139 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Ndieyira, J. W. et al. Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum. Nature Nanotech. 9, 225–232 (2014).

    CAS  Article  Google Scholar 

  22. 22

    Zijlstra, P., Paulo, P. M. R. & Orrit, M. Optical detection of single non-absorbing molecules using the surface plasmon resonance of a gold nanorod. Nature Nanotech. 7, 379–382 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Zheng, G. F., Patolsky, F., Cui Y., Wang, W. U. & Lieber, C. M. Multiplexed electrical detection of cancer markers with nanowire sensor arrays. Nature Biotechnol. 23, 1294–1301 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Xuexin, D. et al. Quantification of the affinities and kinetics of protein interactions using silicon nanowire biosensors. Nature Nanotech. 7, 401–407 (2012).

    Article  Google Scholar 

  25. 25

    Ament, I., Prasad, J., Henkel, A., Schmachtel, S. & Sonnichsen, C. Single unlabeled protein detection on individual plasmonic nanoparticles. Nano Lett. 12, 1092–1095 (2012).

    CAS  Article  Google Scholar 

  26. 26

    Wu, Y., Zhang, D. Y., Yin, P. & Vollmer, F. Ultraspecific and highly sensitive nucleic acid detection by integrating a DNA catalytic network with a label-free microcavity. Small 10, 2067–2076 (2014).

    CAS  Article  Google Scholar 

  27. 27

    Sorgenfrei, S. et al. Label-free single-molecule detection of DNA-hybridization kinetics with a carbon nanotube field-effect transistor. Nature Nanotech. 6, 125–131 (2011).

    Article  Google Scholar 

  28. 28

    He, L. N., Ozdemir, K., Zhu, J. G., Kim, W. & Yang, L. Detecting single viruses and nanoparticles using whispering gallery microlasers. Nature Nanotech. 6, 428–432 (2011).

    CAS  Article  Google Scholar 

  29. 29

    Foreman, M. R., Jin, W. & Vollmer, F. Optimizing detection limits in whispering gallery mode biosensing. Opt. Express 22, 5491–5511 (2014).

    CAS  Article  Google Scholar 

  30. 30

    Foreman, M. R. & Vollmer, F. Level repulsion in hybrid photonic–plasmonic microresonators for enhanced biodetection. Phys. Rev. A 88, 023831 (2013).

    Article  Google Scholar 

  31. 31

    Baaske, M. & Vollmer, F. Optical resonator biosensors: molecular diagnostic and nanoparticle detection on an integrated platform. ChemPhysChem 13, 427–436 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Prodan, E., Radloff, C., Halas, N. J. & Nordlander, P. A hybridization model for the plasmon response of complex nanostructures. Science 302, 419–422 (2003).

    CAS  Article  Google Scholar 

  33. 33

    Huang, X. H., Neretina, S. & El-Sayed, M. A. Gold nanorods: from synthesis and properties to biological and biomedical applications. Adv. Mater. 21, 4880–4910 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Kaplan, A. et al. Finite element simulation of a perturbed axial-symmetric whispering-gallery mode and its use for intensity enhancement with a nanoparticle coupled to a microtoroid. Opt. Express 21, 14169–14180 (2013).

    CAS  Article  Google Scholar 

  35. 35

    Knittel, J., Swaim, J. D., McAuslan, D. L., Brawley, G. A. & Bowen, W. P. Back-scatter based whispering gallery mode sensing. Sci. Rep. 3, 2974 (2013).

    Article  Google Scholar 

  36. 36

    Swaim, J. D., Knittel, J. & Bowen, W. P. Tapered nanofiber trapping of high-refractive-index nanoparticles. Appl. Phys. Lett. 103, 203111 (2013).

    Article  Google Scholar 

  37. 37

    Zhu, J. G., Ozdemir, S. K. & Yang, L. Optical detection of single nanoparticles with a subwavelength fiber-taper. IEEE Photon. Technol. Lett. 23, 1346–1348 (2011).

    CAS  Article  Google Scholar 

  38. 38

    Wilson, K. A., Finch, C. A., Anderson, P., Vollmer, F. & Hickman, J. J. Whispering gallery mode biosensor quantification of fibronectin adsorption kinetics onto alkylsilane monolayers and interpretation of resultant cellular response. Biomaterials 33, 225–236 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Arnold, S., Ramjit, R., Keng, D., Kolchenko, V. & Teraoka, I. MicroParticle photophysics illuminates viral bio-sensing. Faraday Discuss. 137, 65–83 (2008).

    CAS  Article  Google Scholar 

  40. 40

    Topolancik, J. & Vollmer, F. Photoinduced transformations in bacteriorhodopsin membrane monitored with optical microcavities. Biophys. J. 92, 2223–2229 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Noto, M., Vollmer, F., Keng, D., Teraoka, I. & Arnold, S. Nanolayer characterization through wavelength multiplexing of a microsphere resonator. Opt. Lett. 30, 510–512 (2005).

    CAS  Article  Google Scholar 

  42. 42

    Lutti, J., Langbein, W. & Borri, P. A monolithic optical sensor based on whispering-gallery modes in polystyrene microspheres. Appl. Phys. Lett. 93, 151103 (2008).

    Article  Google Scholar 

  43. 43

    Collot, L., Lefevreseguin, V., Brune, M., Raimond, J. M. & Haroche, S. Very high-Q whispering gallery mode resonances observed on fused-silica microspheres. Europhys. Lett. 23, 327–334 (1993).

    CAS  Article  Google Scholar 

  44. 44

    Gorodetsky, M. L., Savchenkov, A. A. & Ilchenko, V. S. Ultimate Q of optical microsphere resonators. Opt. Lett. 21, 453–455 (1996).

    CAS  Article  Google Scholar 

  45. 45

    Gorodetsky, M. L. & Ilchenko, V. S. Optical microsphere resonators: optimal coupling to high-Q whispering-gallery modes. J. Opt. Soc. Am. B 16, 147–154 (1999).

    CAS  Article  Google Scholar 

  46. 46

    Mazzei, A., Gotzinger, S., Menezes, L. D., Sandoghdar, V. & Benson, O. Optimization of prism coupling to high-Q modes in a microsphere resonator using a near-field probe. Opt. Commun. 250, 428–433 (2005).

    CAS  Article  Google Scholar 

  47. 47

    Walker, D. A., Leitsch, E. K., Nap, R. J., Szleifer, I. & Grzybowski, B. A. Geometric curvature controls the chemical patchiness and self-assembly of nanoparticles. Nature Nanotech. 8, 676–681 (2013).

    CAS  Article  Google Scholar 

  48. 48

    Shi, D., Song, C., Jiang, Q., Wang, Z-G. & Ding, B. A facile and efficient method to modify gold nanorods with thiolated DNA at a low pH value. Chem. Commun. 49, 2533–2535 (2013).

    CAS  Article  Google Scholar 

Download references


The authors acknowledge financial support for this work from the Max Planck Society (M.D.B. and F.V.) and the Alexander von Humboldt Foundation (M.R.F.).

Author information




F.V. and M.D.B. conceived and planned the experiments. M.D.B. conducted experimental work and data analysis. M.R.F. performed numerical and theoretical analysis. F.V., M.R.F. and M.D.B. wrote the manuscript.

Corresponding author

Correspondence to Frank Vollmer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary Information (PDF 6856 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Baaske, M., Foreman, M. & Vollmer, F. Single-molecule nucleic acid interactions monitored on a label-free microcavity biosensor platform. Nature Nanotech 9, 933–939 (2014).

Download citation

Further reading


Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research