Super-resolution microscopy as a powerful tool to study complex synthetic materials

Abstract

Understanding the relations between the formation, structure, dynamics and functionality of complex synthetic materials is one of the great challenges in chemistry and nanotechnology and represents the foundation for the rational design of novel materials for a variety of applications. Initially conceived to study biology below the diffraction limit, super-resolution microscopy (SRM) is emerging as a powerful tool for studying synthetic materials owing to its nanometric resolution, multicolour ability and minimal invasiveness. In this Review, we provide an overview of the pioneering studies that use SRM to visualize materials, highlighting exciting recent developments such as experiments in operando, wherein materials, such as biomaterials in a biological environment, are imaged in action. Moreover, the potential and the challenges of the different SRM methods for application in nanotechnology and (bio)materials science are discussed, aiming to guide researchers to select the best SRM approach for their specific purpose.

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Fig. 1: STED imaging of self-assembled supramolecular polymers.
Fig. 2: Polymeric materials studied with SRM.
Fig. 3: Super-resolution imaging of lipid-based materials.
Fig. 4: Super-resolution imaging of DNA origami.
Fig. 5: Super-resolution imaging of metal nanoparticles.
Fig. 6: Interactions between materials and cells or biomolecules can be studied with nanometric resolution using SRM.

References

  1. 1.

    Huang, B., Bates, M. & Zhuang, X. Super-resolution fluorescence microscopy. Annu. Rev. Biochem. 78, 993–1016 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Schermelleh, L., Heintzmann, R. & Leonhardt, H. A guide to super-resolution fluorescence microscopy. J. Cell Biol. 190, 165–175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Möckl, L., Lamb, D. C. & Bräuchle, C. Super-resolved fluorescence microscopy: Nobel Prize in Chemistry 2014 for Eric Betzig, Stefan Hell, and William E. Moerner. Angew. Chem. Int. Ed. 53, 13972–13977 (2014).

    Article  CAS  Google Scholar 

  4. 4.

    Binnig, G., Quate, C. F. & Gerber, C. Atomic force microscope. Phys. Rev. Lett. 56, 930–933 (1986).

    CAS  Article  Google Scholar 

  5. 5.

    Mathys, D. Die Entwicklung der Elektronenmikroskopie vom Bild über die Analyse zum Nanolabor (University of Basel, 2004).

  6. 6.

    Webber, M. J., Appel, E. A., Meijer, E. W. & Langer, R. Supramolecular biomaterials. Nat. Mater. 15, 13–26 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Hyotyla, J. T. & Lim, R. Y. H. in Supramolecular Chemistry: from Molecules to Nanomaterials (eds Steed, J. W. & Gale, P. A.) (John Wiley & Sons, Ltd, 2012).

  8. 8.

    Franken, L. E., Boekema, E. J. & Stuart, M. C. A. Transmission electron microscopy as a tool for the characterization of soft materials: application and interpretation. Adv. Sci. 4, 1600476 (2017).

    Article  CAS  Google Scholar 

  9. 9.

    Lakowicz, J. R. Principles of Fluorescence Spectroscopy (Springer, 2011).

  10. 10.

    Douglass, K. M., Sieben, C., Archetti, A., Lambert, A. & Manley, S. Super-resolution imaging of multiple cells by optimized flat-field epi-illumination. Nat. Photon. 10, 705–708 (2016).

    Article  CAS  Google Scholar 

  11. 11.

    Bates, M., Dempsey, G. T., Chen, K. H. & Zhuang, X. Multicolor super-resolution fluorescence imaging via multi-parameter fluorophore detection. Chemphyschem 13, 99–107 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Jungmann, R. et al. Multiplexed 3D cellular super-resolution imaging with DNA-PAINT and Exchange-PAINT. Nat. Methods 11, 313–318 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lee, S.-H., Shin, J. Y., Lee, A. & Bustamante, C. Counting single photoactivatable fluorescent molecules by photoactivated localization microscopy (PALM). Proc. Natl Acad. Sci. USA 109, 17436–17441 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Venkataramani, V., Herrmannsdörfer, F., Heilemann, M. & Kuner, T. SuReSim: simulating localization microscopy experiments from ground truth models. Nat. Methods 13, 319–321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Habuchi, S. Super-resolution molecular and functional imaging of nanoscale architectures in life and materials science. Front. Bioeng. Biotechnol. 2, 20 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Van Loon, J., Kubarev, A. V. & Roeffaers, M. B. J. Correlating catalyst structure and activity at the nanoscale. ChemNanoMat 4, 6–14 (2018).

    Article  CAS  Google Scholar 

  17. 17.

    Aida, T., Meijer, E. W. & Stupp, S. I. Functional supramolecular polymers. Science 335, 813–817 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Albertazzi, L. et al. Probing exchange pathways in one-dimensional aggregates with super-resolution microscopy. Science 344, 491–495 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Baker, M. B. et al. Consequences of chirality on the dynamics of a water-soluble supramolecular polymer. Nat. Commun. 6, 6234 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Baker, M. B. et al. Exposing differences in monomer exchange rates of multicomponent supramolecular polymers in water. ChemBioChem 17, 207–213 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Aloi, A. et al. Imaging nanostructures by single-molecule localization microscopy in organic solvents. J. Am. Chem. Soc. 138, 2953–2956 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Boott, C. E. et al. In situ visualization of block copolymer self-assembly in organic media by super-resolution fluorescence microscopy. Chemistry 21, 18539–18542 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Adelizzi, B. et al. Painting supramolecular polymers in organic solvents by super-resolution microscopy. ACS Nano 12, 4431–4439 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hendrikse, S. I. S. et al. Controlling and tuning the dynamic nature of supramolecular polymers in aqueous solutions. Chem. Commun. 53, 2279–2282 (2017).

    Article  CAS  Google Scholar 

  25. 25.

    Lee, O.-S., Stupp, S. I. & Schatz, G. C. Atomistic molecular dynamics simulations of peptide amphiphile self-assembly into cylindrical nanofibers. J. Am. Chem. Soc. 133, 3677–3683 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Aloi, A., Vilanova, N., Albertazzi, L. & Voets, I. K. iPAINT: a general approach tailored to image the topology of interfaces with nanometer resolution. Nanoscale 8, 8712–8716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Merdasa, A. et al. Single Lévy states–disorder induced energy funnels in molecular aggregates. Nano Lett. 14, 6774–6781 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Onogi, S. et al. In situ real-time imaging of self-sorted supramolecular nanofibres. Nat. Chem. 8, 743–752 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Tønnesen, J., Inavalli, V. V. G. K. & Nägerl, U. V. Super-resolution imaging of the extracellular space in living brain tissue. Cell 172, 1108–1121 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Schacher, F. H., Rupar, P. A. & Manners, I. Functional block copolymers: nanostructured materials with emerging applications. Angew. Chem. Int. Ed. 51, 7898–7921 (2012).

    Article  CAS  Google Scholar 

  31. 31.

    Qiu, H. et al. Uniform patchy and hollow rectangular platelet micelles from crystallizable polymer blends. Science 352, 697–701 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Ullal, C. K., Schmidt, R., Hell, S. W. & Egner, A. Block copolymer nanostructures mapped by far-field optics. Nano Lett. 9, 2497–2500 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Yan, J. et al. Optical nanoimaging for block copolymer self-assembly. J. Am. Chem. Soc. 137, 2436–2439 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    González-Aramundiz, J. V., Lozano, M. V., Sousa-Herves, A., Fernandez-Megia, E. & Csaba, N. Polypeptides and polyaminoacids in drug delivery. Expert Opin. Drug Deliv. 9, 183–201 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Beun, L. H., Albertazzi, L., van der Zwaag, D., de Vries, R. & Cohen Stuart, M. A. Unidirectional living growth of self-assembled protein nanofibrils revealed by super-resolution microscopy. ACS Nano 10, 4973–4980 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Duro-Castano, A. et al. Capturing “extraordinary” soft-assembled charge-like polypeptides as a strategy for nanocarrier design. Adv. Mater. 29, 1702888 (2017).

    Article  CAS  Google Scholar 

  37. 37.

    Muls, B. et al. Direct measurement of the end-to-end distance of individual polyfluorene polymer chains. Chemphyschem 6, 2286–2294 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Vacha, M. & Habuchi, S. Conformation and physics of polymer chains: a single-molecule perspective. NPG Asia Mater. 2, 134–142 (2010).

    Article  Google Scholar 

  39. 39.

    Aoki, H., Mori, K. & Ito, S. Conformational analysis of single polymer chains in three dimensions by super-resolution fluorescence microscopy. Soft Matter 8, 4390–4395 (2012).

    Article  CAS  Google Scholar 

  40. 40.

    Gramlich, M. W., Bae, J., Hayward, R. C. & Ross, J. L. Fluorescence imaging of nanoscale domains in polymer blends using stochastic optical reconstruction microscopy (STORM). Opt. Express 22, 8438–8450 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    O.Neil, C. E., Jackson, J. M., Shim, S.-H. & Soper, S. A. Interrogating surface functional group heterogeneity of activated thermoplastics using super-resolution fluorescence microscopy. Anal. Chem. 88, 3686–3696 (2016).

    Article  CAS  Google Scholar 

  42. 42.

    Bolinger, J. C., Traub, M. C., Adachi, T. & Barbara, P. F. Ultralong-range polaron-induced quenching of excitons in isolated conjugated polymers. Science 331, 565–567 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Habuchi, S., Onda, S. & Vacha, M. Mapping the emitting sites within a single conjugated polymer molecule. Chem. Commun. 0, 4868–4870 (2009).

    Article  CAS  Google Scholar 

  44. 44.

    Habuchi, S., Onda, S. & Vacha, M. Molecular weight dependence of emission intensity and emitting sites distribution within single conjugated polymer molecules. Phys. Chem. Chem. Phys 13, 1743–1753 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Park, H., Hoang, D. T., Paeng, K. & Kaufman, L. J. Localizing exciton recombination sites in conformationally distinct single conjugated polymers by super-resolution fluorescence imaging. ACS Nano 9, 3151–3158 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Penwell, S. B., Ginsberg, L. D. S. & Ginsberg, N. S. Bringing far-field subdiffraction optical imaging to electronically coupled optoelectronic molecular materials using their endogenous chromophores. J. Phys. Chem. Lett. 6, 2767–2772 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    King, J. T. & Granick, S. Operating organic light-emitting diodes imaged by super-resolution spectroscopy. Nat. Commun. 7, 11691 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Tian, Z., Li, A. D. Q. & Hu, D. Super-resolution fluorescence nanoscopy applied to imaging core–shell photoswitching nanoparticles and their self-assemblies. Chem. Commun. 47, 1258–1260 (2011).

    Article  CAS  Google Scholar 

  49. 49.

    Hu, D., Tian, Z., Wu, W., Wan, W. & Li, A. D. Q. Photoswitchable nanoparticles enable high-resolution cell imaging: PULSAR microscopy. J. Am. Chem. Soc. 130, 15279–15281 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Gong, W.-L. et al. Single-wavelength-controlled in situ dynamic super-resolution fluorescence imaging for block copolymer nanostructures via blue-light-switchable FRAP. Photochem. Photobiol. Sci. 15, 1433–1441 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Nevskyi, O., Sysoiev, D., Oppermann, A., Huhn, T. & Wöll, D. Nanoscopic visualization of soft matter using fluorescent diarylethene photoswitches. Angew. Chem. Int. Ed. 55, 12698–12702 (2016).

    Article  CAS  Google Scholar 

  52. 52.

    Urban, B. E. et al. Subsurface super-resolution imaging of unstained polymer nanostructures. Sci. Rep. 6, 28156 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Barenholz, Y. Doxil®—the first FDA-approved nano-drug: lessons learned. J. Control. Release 160, 117–134 (2012).

    Article  CAS  Google Scholar 

  54. 54.

    Sharonov, A. & Hochstrasser, R. M. Wide-field subdiffraction imaging by accumulated binding of diffusing probes. Proc. Natl Acad. Sci. USA 103, 18911–18916 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Kuo, C. & Hochstrasser, R. M. Super-resolution microscopy of lipid bilayer phases. J. Am. Chem. Soc. 133, 4664–4667 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Bongiovanni, M. N. et al. Multi-dimensional super-resolution imaging enables surface hydrophobicity mapping. Nat. Commun. 7, 13544 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Yan, R., Moon, S., Kenny, S. J. & Xu, K. Spectrally resolved and functional super-resolution microscopy via ultrahigh-throughput single-molecule spectroscopy. Acc. Chem. Res. 51, 697–705 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Boreham, A., Volz, P., Peters, D., Keck, C. M. & Alexiev, U. Determination of nanostructures and drug distribution in lipid nanoparticles by single molecule microscopy. Eur. J. Pharm. Biopharm. 110, 31–38 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Belfiore, L., Spenkelink, L. M., Ranson, M., van Oijen, A. M. & Vine, K. L. Quantification of ligand density and stoichiometry on the surface of liposomes using single-molecule fluorescence imaging. J. Control. Release 278, 80–86 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Rothemund, P. W. K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Saccà, B. & Niemeyer, C. M. DNA origami: the art of folding DNA. Angew. Chem. Int. Ed Engl. 51, 58–66 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Graugnard, E., Hughes, W. L., Jungmann, R., Kostiainen, M. A. & Linko, V. Nanometrology and super-resolution imaging with DNA. MRS Bull. 42, 951–959 (2017).

    Article  CAS  Google Scholar 

  63. 63.

    Steinhauer, C., Jungmann, R., Sobey, T., Simmel, F. & Tinnefeld, P. DNA origami as a nanoscopic ruler for super-resolution microscopy. Angew. Chem. Int. Ed. 48, 8870–8873 (2009).

    Article  CAS  Google Scholar 

  64. 64.

    Schmied, J. J. et al. DNA origami nanopillars as standards for three-dimensional superresolution microscopy. Nano Lett. 13, 781–785 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Schmied, J. J. et al. Fluorescence and super-resolution standards based on DNA origami. Nat. Methods 9, 1133–1134 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Jungmann, R. et al. Single-molecule kinetics and super-resolution microscopy by fluorescence imaging of transient binding on DNA origami. Nano Lett. 10, 4756–4761 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Smith, D. M. et al. A structurally variable hinged tetrahedron framework from DNA origami. J. Nucleic Acids 2011, 360954 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Scheible, M. B. et al. A compact DNA cube with side length 10nm. Small 11, 5200–5205 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Chen, J., Bremauntz, A., Kisley, L., Shuang, B. & Landes, C. F. Super-resolution mbPAINT for optical localization of single-stranded DNA. ACS Appl. Mater. Interfaces 5, 9338–9343 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Knudsen, J. B. et al. Routing of individual polymers in designed patterns. Nat. Nanotechnol. 10, 892–898 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Schueder, F. et al. Multiplexed 3D super-resolution imaging of whole cells using spinning disk confocal microscopy and DNA-PAINT. Nat. Commun. 8, 2090 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Auer, A., Strauss, M. T., Schlichthaerle, T. & Jungmann, R. Fast, background-free DNA-PAINT imaging using FRET-based probes. Nano Lett. 17, 6428–6434 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Karathanasis, C., Fricke, F., Hummer, G. & Heilemann, M. Molecule counts in localization microscopy with organic fluorophores. Chemphyschem 18, 942–948 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Beater, S., Holzmeister, P., Pibiri, E., Lalkens, B. & Tinnefeld, P. Choosing dyes for cw-STED nanoscopy using self-assembled nanorulers. Phys. Chem. Chem. Phys 16, 6990–6996 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Dai, M., Jungmann, R. & Yin, P. Optical imaging of individual biomolecules in densely packed clusters. Nat. Nanotechnol. 11, 798–807 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Delcanale, P., Miret-Ontiveros, B., Arista-Romero, M., Pujals, S. & Albertazzi, L. Nanoscale mapping functional sites on nanoparticles by points accumulation for imaging in nanoscale topography (PAINT). ACS Nano 12, 7629–7637 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Harke, B., Ullal, C. K., Keller, J. & Hell, S. W. Three-dimensional nanoscopy of colloidal crystals. Nano Lett. 8, 1309–1313 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Hauser, M. et al. Correlative super-resolution microscopy: new dimensions and new opportunities. Chem. Rev. 117, 7428–7456 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Bon, P. et al. Three-dimensional nanometre localization of nanoparticles to enhance super-resolution microscopy. Nat. Commun. 6, 7764 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Xu, W., Kong, J. S., Yeh, Y.-T. E. & Chen, P. Single-molecule nanocatalysis reveals heterogeneous reaction pathways and catalytic dynamics. Nat. Mater. 7, 992–996 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Chen, T., Zhang, Y. & Xu, W. Single-molecule nanocatalysis reveals catalytic activation energy of single nanocatalysts. J. Am. Chem. Soc. 138, 12414–12421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Zhou, X., Choudhary, E., Andoy, N. M., Zou, N. & Chen, P. Scalable parallel screening of catalyst activity at the single-particle level and subdiffraction resolution. ACS Catal. 3, 1448–1453 (2013).

    Article  CAS  Google Scholar 

  83. 83.

    Zhou, X. et al. Quantitative super-resolution imaging uncovers reactivity patterns on single nanocatalysts. Nat. Nanotechnol. 7, 237–241 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Cang, H. et al. Probing the electromagnetic field of a 15-nanometre hotspot by single molecule imaging. Nature 469, 385–388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Xu, W., Kong, J. S. & Chen, P. Probing the catalytic activity and heterogeneity of Au-nanoparticles at the single-molecule level. Phys. Chem. Chem. Phys 11, 2767–2778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Zhou, X., Xu, W., Liu, G., Panda, D. & Chen, P. Size-dependent catalytic activity and dynamics of gold nanoparticles at the single-molecule level. J. Am. Chem. Soc. 132, 138–146 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Chen, T., Zhang, Y. & Xu, W. Size-dependent catalytic kinetics and dynamics of Pd nanocubes: a single-particle study. Phys. Chem. Chem. Phys 18, 22494–22502 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Shen, H., Zhou, X., Zou, N. & Chen, P. Single-molecule kinetics reveals a hidden surface reaction intermediate in single-nanoparticle catalysis. J. Phys. Chem. C 118, 26902–26911 (2014).

    Article  CAS  Google Scholar 

  89. 89.

    Han, K. S., Liu, G., Zhou, X., Medina, R. E. & Chen, P. How does a single Pt nanocatalyst behave in two different reactions? a single-molecule study. Nano Lett. 12, 1253–1259 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Wilson, A. J., Molina, N. Y. & Willets, K. A. Modification of the electrochemical properties of nile blue through covalent attachment to gold as revealed by electrochemistry and SERS. J. Phys. Chem. C 120, 21091–21098 (2016).

    Article  CAS  Google Scholar 

  91. 91.

    Wilson, A. J. & Willets, K. A. Unforeseen distance-dependent SERS spectroelectrochemistry from surface-tethered Nile Blue: the role of molecular orientation. Analyst 141, 5144–5151 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Titus, E. J., Weber, M. L., Stranahan, S. M. & Willets, K. A. Super-resolution SERS imaging beyond the single-molecule limit: an isotope-edited approach. Nano Lett. 12, 5103–5110 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Willets, K. A., Wilson, A. J., Sundaresan, V. & Joshi, P. B. Super-resolution imaging and plasmonics. Chem. Rev. 117, 7538–7582 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Blythe, K. L., Mayer, K. M., Weber, M. L. & Willets, K. A. Ground state depletion microscopy for imaging interactions between gold nanowires and fluorophore-labeled ligands. Phys. Chem. Chem. Phys 15, 4136–4145 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Lim, K. et al. Nanostructure-induced distortion in single-emitter microscopy. Nano Lett. 16, 5415–5419 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Thompson, R. E., Larson, D. R. & Webb, W. W. Precise nanometer localization analysis for individual fluorescent probes. Biophys. J. 82, 2775–2783 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Lin, H. et al. Mapping of surface-enhanced fluorescence on metal nanoparticles using super-resolution photoactivation localization microscopy. Chemphyschem 13, 973–981 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Simoncelli, S., Roberti, M. J., Araoz, B., Bossi, M. L. & Aramendía, P. F. Mapping the fluorescence performance of a photochromic–fluorescent system coupled with gold nanoparticles at the single-molecule–single-particle level. J. Am. Chem. Soc. 136, 6878–6880 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Fu, B., Flynn, J. D., Isaacoff, B. P., Rowland, D. J. & Biteen, J. S. Super-resolving the distance-dependent plasmon-enhanced fluorescence of single dye and fluorescent protein molecules. J. Phys. Chem. C 119, 19350–19358 (2015).

    Article  CAS  Google Scholar 

  100. 100.

    Johlin, E. et al. Super-resolution imaging of light–matter interactions near single semiconductor nanowires. Nat. Commun. 7, 13950 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Simoncelli, S., Li, Y., Cortés, E. & Maier, S. A. Nanoscale control of molecular self-assembly induced by plasmonic hot-electron dynamics. ACS Nano 12, 2184–2192 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Taylor, A., Verhoef, R., Beuwer, M., Wang, Y. & Zijlstra, P. All-optical imaging of gold nanoparticle geometry using super-resolution microscopy. J. Phys. Chem. C Nanomater. Interfaces 122, 2336–2342 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Yuan, H. et al. Imaging heterogeneously distributed photo-active traps in perovskite single crystals. Adv. Mater. 30, 1705494 (2018).

    Article  CAS  Google Scholar 

  104. 104.

    Ristanovic´, Z. et al. High-resolution single-molecule fluorescence imaging of zeolite aggregates within real-life fluid catalytic cracking particles. Angew. Chem. Int. Ed. 54, 1836–1840 (2015).

    Article  CAS  Google Scholar 

  105. 105.

    Ristanovic´, Z. et al. Quantitative 3D fluorescence imaging of single catalytic turnovers reveals spatiotemporal gradients in reactivity of zeolite H-ZSM-5 crystals upon steaming. J. Am. Chem. Soc. 137, 6559–6568 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Roeffaers, M. B. J. et al. Super-resolution reactivity mapping of nanostructured catalyst particles. Angew. Chem. Int. Ed. 48, 9285–9289 (2009).

    Article  CAS  Google Scholar 

  107. 107.

    Hendriks, F. C. et al. Integrated transmission electron and single-molecule fluorescence microscopy correlates reactivity with ultrastructure in a single catalyst particle. Angew. Chem. Int. Ed. 57, 257–261 (2018).

    Article  CAS  Google Scholar 

  108. 108.

    Roeffaers, M. B. J. et al. Spatially resolved observation of crystal-face-dependent catalysis by single turnover counting. Nature 439, 572–575 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Cavalieri, F. et al. Redox-sensitive PEG–polypeptide nanoporous particles for survivin silencing in prostate cancer cells. Biomacromolecules 16, 2168–2178 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Teplensky, M. H. et al. Temperature treatment of highly porous zirconium-containing metal–organic frameworks extends drug delivery release. J. Am. Chem. Soc. 139, 7522–7532 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Tolstik, E. et al. Studies of silicon nanoparticles uptake and biodegradation in cancer cells by Raman spectroscopy. Nanomedicine 12, 1931–1940 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Tolstik, E. et al. Linear and non-linear optical imaging of cancer cells with silicon nanoparticles. Int. J. Mol. Sci. 17, E1536 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Guggenheim, E. J. et al. Comparison of confocal and super-resolution reflectance imaging of metal oxide nanoparticles. PLOS ONE 11, e0159980 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Schübbe, S. et al. Size-dependent localization and quantitative evaluation of the intracellular migration of silica nanoparticles in caco-2 cells. Chem. Mater. 24, 914–923 (2012).

    Article  CAS  Google Scholar 

  115. 115.

    Schübbe, S., Cavelius, C., Schumann, C., Koch, M. & Kraegeloh, A. STED microscopy to monitor agglomeration of silica particles inside A549 cells. Adv. Eng. Mater. 12, 417–422 (2010).

    Article  CAS  Google Scholar 

  116. 116.

    Peuschel, H., Ruckelshausen, T., Cavelius, C. & Kraegeloh, A. Quantification of internalized silica nanoparticles via STED microscopy. Biomed Res. Int. 2015, 961208 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Leménager, G., Luca, E. D., Sun, Y.-P. & Pompa, P. P. Super-resolution fluorescence imaging of biocompatible carbon dots. Nanoscale 6, 8617–8623 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Shang, L. et al. Protein-based fluorescent nanoparticles for super-resolution STED imaging of live cells. Chem. Sci. 8, 2396–2400 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Tzeng, Y.-K. et al. Superresolution imaging of albumin-conjugated fluorescent nanodiamonds in cells by stimulated emission depletion. Angew. Chem. Int. Ed. 50, 2262–2265 (2011).

    Article  CAS  Google Scholar 

  120. 120.

    Wäldchen, S., Lehmann, J., Klein, T., van de Linde, S. & Sauer, M. Light-induced cell damage in live-cell super-resolution microscopy. Sci. Rep. 5, 15348 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Heine, J. et al. Adaptive-illumination STED nanoscopy. Proc. Natl Acad. Sci. USA 114, 9797–9802 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Göttfert, F. et al. Strong signal increase in STED fluorescence microscopy by imaging regions of subdiffraction extent. Proc. Natl Acad. Sci. USA 114, 2125–2130 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    van der Zwaag, D. et al. Super resolution imaging of nanoparticles cellular uptake and trafficking. ACS Appl. Mater. Interfaces 8, 6391–6399 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    De Koker, S. et al. Engineering polymer hydrogel nanoparticles for lymph node-targeted delivery. Angew. Chem. Int. Ed. 55, 1334–1339 (2016).

    Article  CAS  Google Scholar 

  125. 125.

    Li, Y., Shang, L. & Nienhaus, G. U. Super-resolution imaging-based single particle tracking reveals dynamics of nanoparticle internalization by live cells. Nanoscale 8, 7423–7429 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Geddes, C. D., Parfenov, A., Gryczynski, I. & Lakowicz, J. R. Luminescent blinking of gold nanoparticles. Chem. Phys. Lett. 380, 269–272 (2003).

    Article  CAS  Google Scholar 

  127. 127.

    Kuno, M., Fromm, D. P., Hamann, H. F., Gallagher, A. & Nesbitt, D. J. “On”/“off” fluorescence intermittency of single semiconductor quantum dots. J. Chem. Phys. 115, 1028–1040 (2001).

    Article  CAS  Google Scholar 

  128. 128.

    Moser, F. et al. Cellular uptake of gold nanoparticles and their behavior as labels for localization microscopy. Biophys. J. 110, 947–953 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Wegner, W. et al. In vivo mouse and live cell STED microscopy of neuronal actin plasticity using far-red emitting fluorescent proteins. Sci. Rep. 7, 11781 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Wegner, W., Mott, A. C., Grant, S. G. N., Steffens, H. & Willig, K. I. In vivo STED microscopy visualizes PSD95 sub-structures and morphological changes over several hours in the mouse visual cortex. Sci. Rep. 8, 219 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Cui, J. et al. Immobilized particle imaging for quantification of nano- and microparticles. Langmuir 32, 3532–3540 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Ardizzone, A. et al. Nanostructuring lipophilic dyes in water using stable vesicles, quatsomes, as scaffolds and their use as probes for bioimaging. Small 14, 1703851 (2018).

    Article  CAS  Google Scholar 

  133. 133.

    Krivitsky, A. et al. Amphiphilic poly(α)glutamate polymeric micelles for systemic administration of siRNA to tumors. Nanomedicine 14, 303–315 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Chen, X. et al. Analysing intracellular deformation of polymer capsules using structured illumination microscopy. Nanoscale 8, 11924–11931 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Chen, X. et al. Probing cell internalisation mechanics with polymer capsules. Nanoscale 8, 17096–17101 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    Article  CAS  Google Scholar 

  137. 137.

    Ke, P. C., Lin, S., Parak, W. J., Davis, T. P. & Caruso, F. A. Decade of the protein corona. ACS Nano 11, 11773–11776 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Feiner-Gracia, N. et al. Super-resolution microscopy unveils dynamic heterogeneities in nanoparticle protein corona. Small 13, 1701631 (2017).

    Article  CAS  Google Scholar 

  139. 139.

    Clemments, A. M., Botella, P. & Landry, C. C. Spatial mapping of protein adsorption on mesoporous silica nanoparticles by stochastic optical reconstruction microscopy. J. Am. Chem. Soc. 139, 3978–3981 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Runa, S., Lakadamyali, M., Kemp, M. L. & Payne, C. K. TiO2 nanoparticle-induced oxidation of the plasma membrane: importance of the protein corona. J. Phys. Chem. B 121, 8619–8625 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Oria, R. et al. Force loading explains spatial sensing of ligands by cells. Nature 552, 219–224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Chelladurai, R., Debnath, K., Jana, N. R. & Basu, J. K. Nanoscale heterogeneities drive enhanced binding and anomalous diffusion of nanoparticles in model biomembranes. Langmuir 34, 1691–1699 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Chmyrov, A. et al. Nanoscopy with more than 100,000 ‘doughnuts’. Nat. Methods 10, 737–740 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Winter, P. W. et al. Incoherent structured illumination improves optical sectioning and contrast in multiphoton super-resolution microscopy. Opt. Express 23, 5327–5334 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Izeddin, I. et al. PSF shaping using adaptive optics for three-dimensional single-molecule super-resolution imaging and tracking. Opt. Express 20, 4957–4967 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Uno, S. et al. A spontaneously blinking fluorophore based on intramolecular spirocyclization for live-cell super-resolution imaging. Nat. Chem. 6, 681–689 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Hsiao, W. W.-W., Hui, Y. Y., Tsai, P.-C. & Chang, H.-C. Fluorescent nanodiamond: a versatile tool for long-term cell tracking, super-resolution imaging, and nanoscale temperature sensing. Acc. Chem. Res. 49, 400–407 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Kianinia, M. et al. All-optical control and super-resolution imaging of quantum emitters in layered materials. Nat. Commun. 9, 874 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Betzig, E. et al. Imaging intracellular fluorescent proteins at nanometer resolution. Science 313, 1642–1645 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Watanabe, S. et al. Protein localization in electron micrographs using fluorescence nanoscopy. Nat. Methods 8, 80–84 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Kopek, B. G., Shtengel, G., Xu, C. S., Clayton, D. A. & Hess, H. F. Correlative 3D superresolution fluorescence and electron microscopy reveal the relationship of mitochondrial nucleoids to membranes. Proc. Natl Acad. Sci. USA 109, 6136–6141 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Kopek, B. G., Shtengel, G., Grimm, J. B., Clayton, D. A. & Hess, H. F. Correlative photoactivated localization and scanning electron microscopy. PLOS ONE 8, e77209 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Suleiman, H. et al. Nanoscale protein architecture of the kidney glomerular basement membrane. eLife 2, e01149 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Sochacki, K. A., Shtengel, G., van Engelenburg, S. B., Hess, H. F. & Taraska, J. W. Correlative super-resolution fluorescence and metal-replica transmission electron microscopy. Nat. Methods 11, 305–308 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Engelenburg, S. B. V. et al. Distribution of ESCRT machinery at HIV assembly sites reveals virus scaffolding of ESCRT subunits. Science 343, 653–656 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Perkovic, M. et al. Correlative light- and electron microscopy with chemical tags. J. Struct. Biol. 186, 205–213 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Chang, Y.-W. et al. Correlated cryogenic photoactivated localization microscopy and cryo-electron tomography. Nat. Methods 11, 737–739 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Löschberger, A., Franke, C., Krohne, G., van de Linde, S. & Sauer, M. Correlative super-resolution fluorescence and electron microscopy of the nuclear pore complex with molecular resolution. J. Cell Sci. 127, 4351–4355 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Jord, A. A. et al. Centriole amplification by mother and daughter centrioles differs in multiciliated cells. Nature 516, 104–107 (2014).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Paez-Segala, M. G. et al. Fixation-resistant photoactivatable fluorescent proteins for CLEM. Nat. Methods 12, 215–218 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Johnson, E. et al. Correlative in-resin super-resolution and electron microscopy using standard fluorescent proteins. Sci. Rep. 5, 9583 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Kim, D. et al. Correlative stochastic optical reconstruction microscopy and electron microscopy. PLOS ONE 10, e0124581 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Wojcik, M., Hauser, M., Li, W., Moon, S. & Xu, K. Graphene-enabled electron microscopy and correlated super-resolution microscopy of wet cells. Nat. Commun. 6, 7384 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Liu, B. et al. Three-dimensional super-resolution protein localization correlated with vitrified cellular context. Sci. Rep. 5, 13017 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Harke, B., Chacko, J. V., Haschke, H., Canale, C. & Diaspro, A. A novel nanoscopic tool by combining AFM with STED microscopy. Opt. Nanosc. 1, 3 (2012).

    Article  Google Scholar 

  166. 166.

    Odermatt, P. D. et al. High-resolution correlative microscopy: bridging the gap between single molecule localization microscopy and atomic force microscopy. Nano Lett. 15, 4896–4904 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Chacko, J. V., Canale, C., Harke, B. & Diaspro, A. Sub-diffraction nano manipulation using STED AFM. PLOS ONE 8, e66608 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Monserrate, A., Casado, S. & Flors, C. Correlative atomic force microscopy and localization-based super-resolution microscopy: revealing labelling and image reconstruction artefacts. Chemphyschem 15, 647–650 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Chacko, J. V., Zanacchi, F. C. & Diaspro, A. Probing cytoskeletal structures by coupling optical superresolution and AFM techniques for a correlative approach. Cytoskeleton (Hoboken) 70, 729–740 (2013).

    Article  CAS  Google Scholar 

  170. 170.

    Frasconi, M. et al. Multi-functionalized carbon nano-onions as imaging probes for cancer cells. Chemistry 21, 19071–19080 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Fenaroli, F. et al. Nanoparticles as drug delivery system against tuberculosis in zebrafish embryos: direct visualization and treatment. ACS Nano 8, 7014–7026 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Othman, B. A. et al. Correlative light-electron microscopy shows RGD-targeted ZnO nanoparticles dissolve in the intracellular environment of triple negative breast cancer cells and cause apoptosis with intratumor heterogeneity. Adv. Healthc. Mater. 5, 1310–1325 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Reifarth, M. et al. Cellular uptake of PLA nanoparticles studied by light and electron microscopy: synthesis, characterization and biocompatibility studies using an iridium(III) complex as correlative label. Chem. Commun. 52, 4361–4364 (2016).

    Article  CAS  Google Scholar 

  174. 174.

    Kempen, P. J. et al. A correlative optical microscopy and scanning electron microscopy approach to locating nanoparticles in brain tumors. Micron 68, 70–76 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Gustafsson, M. G. L. Surpassing the lateral resolution limit by a factor of two using structured illumination microscopy. J. Microsc. 198, 82–87 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Godin, A. G., Lounis, B. & Cognet, L. Super-resolution microscopy approaches for live cell imaging. Biophys. J. 107, 1777–1784 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Gustafsson, M. G. L. Nonlinear structured-illumination microscopy: wide-field fluorescence imaging with theoretically unlimited resolution. Proc. Natl Acad. Sci. USA 102, 13081–13086 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    York, A. G. et al. Instant super-resolution imaging in live cells and embryos via analog image processing. Nat. Methods 10, 1122–1126 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Hell, S. W. & Wichmann, J. Breaking the diffraction resolution limit by stimulated emission: stimulated-emission-depletion fluorescence microscopy. Opt. Lett. 19, 780–782 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. 180.

    Klar, T. A., Jakobs, S., Dyba, M., Egner, A. & Hell, S. W. Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission. Proc. Natl Acad. Sci. USA 97, 8206–8210 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. 181.

    Gustafsson, M. G. L. et al. Three-dimensional resolution doubling in wide-field fluorescence microscopy by structured illumination. Biophys. J. 94, 4957–4970 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Dyba, M. & Hell, S. W. Focal spots of size λ / 23 open up far-field florescence microscopy at 33 nm axial resolution. Phys. Rev. Lett. 88, 163901 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Hess, S. T., Girirajan, T. P. K. & Mason, M. D. Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys. J. 91, 4258–4272 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Rust, M. J., Bates, M. & Zhuang, X. Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat. Methods 3, 793–796 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Jones, S. A., Shim, S.-H., He, J. & Zhuang, X. Fast, three-dimensional super-resolution imaging of live cells. Nat. Methods 8, 499–505 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    York, A. G., Ghitani, A., Vaziri, A., Davidson, M. W. & Shroff, H. Confined activation and subdiffractive localization enables whole-cell PALM with genetically expressed probes. Nat. Methods 8, 327–333 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Heilemann, M. et al. Subdiffraction-resolution fluorescence imaging with conventional fluorescent probes. Angew. Chem. Int. Ed. 47, 6172–6176 (2008).

    Article  CAS  Google Scholar 

  188. 188.

    Huang, B., Wang, W., Bates, M. & Zhuang, X. Three-dimensional super-resolution imaging by stochastic optical reconstruction microscopy. Science 319, 810–813 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Lin, C. et al. Submicrometre geometrically encoded fluorescent barcodes self-assembled from DNA. Nat. Chem. 4, 832–839 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Iinuma, R. et al. Polyhedra self-assembled from DNA tripods and characterized with 3D DNA-PAINT. Science 344, 65–69 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the Spanish Ministry of Economy, Industry and Competitiveness through the project SAF2016-75241-R, the Generalitat de Catalunya through the Centres de Recerca de Catalunya (CERCA) programme, the EuroNanoMed II platform through the NanoVax project, the Obra Social La Caixa foundation and the European Research Council (ERC-StG-757397). The useful discussions with the entire Nanoscopy for Nanomedicine group are gratefully acknowledged.

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Glossary

Abbe’s criteria

Criteria that state the resolution that can be obtained in principle, considering the diffraction of light. Ernst Abbe described in 1873 that by using light with a wavelength λ travelling through a medium of refractive index n and focused with a half-angle θ, the minimum resolution possible is λ/2nsin θ.

Far-field optical techniques

Techniques that make use of optical microscopes in which light does not pass through subwavelength features.

4Pi microscopy

A fluorescence technique in which two objective lenses are focused to the same spatial location to achieve improved axial resolution.

Recombinant proteins

Translated products of the expression of recombinant DNA non-native to living cells (such as bacteria, mammalian and yeast).

Stepwise photobleaching

The sequential loss of the fluorescence of individual molecules, resulting in a series of distinguishable steps that provide information about the number of fluorophores present.

Transmission diffraction grating

A device with a periodic structure that diffracts incident light into different directions.

Protein corona

The layer of adsorbed protein on the surface of a nanoparticle exposed to biological fluids such as blood. It can be divided into hard corona, stably bound proteins and soft corona, which is loosely and reversibly bound to the surface.

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Pujals, S., Feiner-Gracia, N., Delcanale, P. et al. Super-resolution microscopy as a powerful tool to study complex synthetic materials. Nat Rev Chem 3, 68–84 (2019). https://doi.org/10.1038/s41570-018-0070-2

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