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Cell entry of one-dimensional nanomaterials occurs by tip recognition and rotation


Materials with high aspect ratio, such as carbon nanotubes and asbestos fibres, have been shown to cause length-dependent toxicity in certain cells because these long materials prevent complete ingestion and this frustrates the cell1,2,3. Biophysical models have been proposed to explain how spheres and elliptical nanostructures enter cells4,5,6,7,8, but one-dimensional nanomaterials have not been examined. Here, we show experimentally and theoretically that cylindrical one-dimensional nanomaterials such as carbon nanotubes enter cells through the tip first. For nanotubes with end caps or carbon shells at their tips, uptake involves tip recognition through receptor binding, rotation that is driven by asymmetric elastic strain at the tube–bilayer interface, and near-vertical entry. The precise angle of entry is governed by the relative timescales for tube rotation and receptor diffusion. Nanotubes without caps or shells on their tips show a different mode of membrane interaction, posing an interesting question as to whether modifying the tips of tubes may help avoid frustrated uptake by cells.

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Figure 1: Experimental evidence for energy-dependent tip-entry mode in the cellular interactions of one-dimensional nanomaterials.
Figure 2: Course-grained molecular dynamics simulation model.
Figure 3: Time sequence of CGMD simulation results showing a MWCNT penetrating the cell membrane at an initial entry angle of θ0 = 45°.
Figure 4: Analytical model of a MWCNT entering cell.


  1. Poland, C. A. et al. Carbon nanotubes introduced into the abdominal cavity of mice show asbestos-like pathogenicity in a pilot study. Nature Nanotech. 3, 423–428 (2008).

    Article  CAS  Google Scholar 

  2. Donaldson, K., Murphy, F. A., Duffin, R. & Poland, C. A. Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part. Fibre Toxicol. 7, 5 (2010).

    Article  Google Scholar 

  3. Brown, D. M. et al. An in vitro study of the potential of carbon nanotubes and nanofibres to induce inflammatory mediators and frustrated phagocytosis. Carbon 45, 1743–1756 (2007).

    Article  CAS  Google Scholar 

  4. Gao, H. J., Shi, W. D. & Freund, L. B. Mechanics of receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 102, 9469–9474 (2005).

    Article  CAS  Google Scholar 

  5. Decuzzi, P. & Ferrari, M. The receptor-mediated endocytosis of nonspherical particles. Biophys. J. 94, 3790–3797 (2008).

    Article  CAS  Google Scholar 

  6. Chen, H., Langer, R. & Edwards, D. A. A film tension theory of phagocytosis. J. Colloid Interface Sci. 190, 118–133 (1997).

    Article  CAS  Google Scholar 

  7. Yang, K. & Ma Y. Q. Computer simulation of the translocation of nanoparticles with different shapes across a lipid bilayer. Nature Nanotech. 5, 579–583 (2010).

    Article  CAS  Google Scholar 

  8. Zhang, S., Li, J., Lykotrafitis, G., Bao, G. & Suresh, S. Size-dependent endocytosis of nanoparticles. Adv. Mater. 21, 419–424 (2009).

    Article  Google Scholar 

  9. Kostarelos, K., Bianco, A. & Prato, M. Promises, facts and challenges for carbon nanotubes in imaging and therapeutics. Nature Nanotech. 4, 627–633 (2009).

    Article  CAS  Google Scholar 

  10. Cheung, W., Pontoriero, F., Taratula, O., Chen, A. M. & He, H. DNA and carbon nanotubes as medicine. Adv. Drug. Deliv. Rev. 62, 633–649 (2010).

    Article  CAS  Google Scholar 

  11. Sanchez, V. C., Pietruska, J. R., Miselis, N. R., Hurt, R. H. & Kane, A. B. Biopersistence and potential adverse health impacts of fibrous nanomaterials: what have we learned from asbestos? Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 5, 511–529 (2009).

    Article  Google Scholar 

  12. Nagai, H. & Toyokuni, S. Biopersistent fiber-induced inflammation and carcinogenesis: lessons learned from asbestos toward safety of fibrous nanomaterials. Arch. Biochem. Biophys. 502, 1–7 (2010).

    Article  CAS  Google Scholar 

  13. Unfried, K. et al. Cellular responses to nanoparticles: target structures and mechanisms. Nanotoxicology 1, 52–71 (2007).

    Article  CAS  Google Scholar 

  14. MacCorkle, R. A., Sluttery, S. D., Nash, D. R. & Brinkley, B. R. Intracellular protein binding to asbestos induces aneuploidy in human lung fibroblasts. Cell Motil. Cytoskel. 63, 646–657 (2006).

    Article  CAS  Google Scholar 

  15. Champion, J. A. & Mitragotri, S. Role of target geometry in phagocytosis. Proc. Natl Acad. Sci. USA 103, 4930–4934 (2006).

    Article  CAS  Google Scholar 

  16. Yang, S. et al. Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice. Toxicol. Lett. 181, 182–189 (2008).

    Article  CAS  Google Scholar 

  17. Porter, D. W. et al. Mouse pulmonary dose and time course responses induced by exposure to multi-walled carbon nanotubes. Toxicology 269, 136–147 (2010).

    Article  CAS  Google Scholar 

  18. Resnick, D., Freedman, N. J., Xu, S. & Krieger, M. Secreted extracellular domains of macrophage scavenger receptors form elongated trimers, which specifically bind crocidolite asbestos. J. Biol. Chem. 5, 3538–3545 (1993).

    Google Scholar 

  19. Hirano, S., Kanno, S. & Furuyama, A. Multi-walled carbon nanotubes injure the plasma membrane of macrophages. Toxicol. Appl. Pharmacol. 232, 244–251 (2008).

    Article  CAS  Google Scholar 

  20. Zhang, L. W. & Monteiro-Riviere, N. A. Lectins modulate multi-walled carbon nanotubes cellular uptake in human epidermal keratinocytes. Toxicol. Vitro 24, 546–551 (2010).

    Article  CAS  Google Scholar 

  21. Wu, J., Nantz, M. H. & Zern, M. A. Targeting hepatocytes for drug and gene delivery: emerging novel approaches and applications. Front. Biosci. 7, 717–725 (2002).

    Google Scholar 

  22. Moghimi, S. M. & Hunter, A. C. Recognition by macrophages and liver cells of opsonized phospholipid vesicles and phospholipid headgroups. Pharmacol. Res. 18, 1–8 (2001).

    Article  CAS  Google Scholar 

  23. Wu, J., Liu, W., Koenig, K., Idell, S. & Broaddus, V. C. Vitronectin adsorption to chrysotile asbestos increases fiber phagocytosis and toxicity for mesothelial cells. Am. J. Physiol. Lung Cell Mol. Physiol. 279, L916–L923 (2000).

    Article  CAS  Google Scholar 

  24. Pande, P., Mosleh, T. A. & Aust, A. E. Role of alpha v beta 5 integrin receptor in endocytosis of crocidolite and its effect on intracellular glutathione levels in human lung epithelial (A 549) cells. Toxicol. Appl. Pharmacol. 210, 70–77 (2006).

    Article  CAS  Google Scholar 

  25. Nelson, P. Biological Physics: Energy, Information, Life (Freeman, 2003).

  26. Hamilton, R. F. Jr et al. Particle length-dependent titanium dioxide nanomaterials toxicity and bioactivity. Part. Fibre Toxicol. 6, 35 (2009).

    Article  Google Scholar 

  27. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    Article  CAS  Google Scholar 

  28. Xu, Y. et al. Nona-Arginine facilitates delivery of quantum dots into cells via multiple pathways. J. Biomed. Biotechnol. 2010, 948543 (2010).

    Google Scholar 

  29. Reynwar, B. J. et al. Aggregation and vesiculation of membrane proteins by curvature-mediated interactions. Nature 447, 461–464 (2007).

    Article  CAS  Google Scholar 

  30. Tirado, M. M., Martinez, C. L. & de la Torre, J. G. Comparison of theories for the translational and rotational diffusion coefficients of rod-like macromolecules. Application to short DNA fragments. J. Chem. Phys. 81, 2047–2052 (1984).

    Article  Google Scholar 

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This work was supported by the National Science Foundation (NSF; grant CMMI-1028530), the US Department of Commerce, National Institute of Standards and Technology as part of the Rhode Island Consortium for Nanoscience and Nanotechnology, the National Institute of Environmental Health Sciences (NIEHS) Superfund Research Program P42 ES013660, and an R01 grant (ES016178) from the NIEHS. The simulations reported were performed on NSF TeraGrid resources provided by National Institute for Computational Sciences (NICS; under MCB090194) and resources from the Supercomputing Center of Chinese Academy of Sciences (SCCAS) and Shanghai Supercomputer Center (SSC). The authors thank P. Weston in the Molecular Pathology Core at Brown University for her assistance with electron microscopic sample preparation and imaging and F. Guo for measurement of MWCNT zeta potentials.

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X.H.S., A.v.d.B., R.H.H., A.B.K. and H.J.G. conceived and designed the experiments and simulations. X.H.S. performed the simulations. A.v.d.B. performed the experiments. X.H.S., A.v.d.B., R.H.H., A.B.K. and H.J.G. analysed the data. X.H.S., A.v.d.B., R.H.H., A.B.K. and H.J.G. co-wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to Agnes B. Kane or Huajian Gao.

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The authors declare no competing financial interests.

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Shi, X., von dem Bussche, A., Hurt, R. et al. Cell entry of one-dimensional nanomaterials occurs by tip recognition and rotation. Nature Nanotech 6, 714–719 (2011).

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