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.

Mechanism of hard-nanomaterial clearance by the liver


The liver and spleen are major biological barriers to translating nanomedicines because they sequester the majority of administered nanomaterials and prevent delivery to diseased tissue. Here we examined the blood clearance mechanism of administered hard nanomaterials in relation to blood flow dynamics, organ microarchitecture and cellular phenotype. We found that nanomaterial velocity reduces 1,000-fold as they enter and traverse the liver, leading to 7.5 times more nanomaterial interaction with hepatic cells relative to peripheral cells. In the liver, Kupffer cells (84.8 ± 6.4%), hepatic B cells (81.5 ± 9.3%) and liver sinusoidal endothelial cells (64.6 ± 13.7%) interacted with administered PEGylated quantum dots, but splenic macrophages took up less material (25.4 ± 10.1%) due to differences in phenotype. The uptake patterns were similar for two other nanomaterial types and five different surface chemistries. Potential new strategies to overcome off-target nanomaterial accumulation may involve manipulating intra-organ flow dynamics and modulating the cellular phenotype to alter hepatic cell interactions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Distribution of quantum dots in the liver following systemic intravascular injection.
Figure 2: Nanomaterial sequestration in the liver versus in the systemic circulation: mathematical modelling and in vivo results.
Figure 3: Characterization of in vivo quantum dot uptake in the liver.
Figure 4: In vivo and in vitro results for quantum dot uptake in the liver versus in the spleen.
Figure 5: Nanomaterial uptake by Kupffer cells can be reduced by manipulating flow rate and cellular phenotype.
Figure 6: Mechanism of nanomaterial transport in the liver.


  1. 1

    Kim, B. Y., Rutka, J. T. & Chan, W. C. Nanomedicine. N. Engl. J. Med. 363, 2434–2443 (2010).

    CAS  Article  Google Scholar 

  2. 2

    Veiseh, O., Tang, B. C., Whitehead, K. A., Anderson, D. G. & Langer, R. Managing diabetes with nanomedicine: challenges and opportunities. Nat. Rev. Drug. Discov. 14, 45–57 (2014).

    Article  Google Scholar 

  3. 3

    Mulder, W. J. M., Jaffer, F. A., Fayad, Z. A. & Nahrendorf, M. Imaging and nanomedicine in inflammatory atherosclerosis. Sci. Transl. Med. 6, 239sr1 (2014).

    Article  Google Scholar 

  4. 4

    Nasongkla, N. et al. Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems. Nano Lett. 6, 2427–2430 (2006).

    CAS  Article  Google Scholar 

  5. 5

    Jaiswal, J. K., Mattoussi, H., Mauro, J. M. & Simon, S. M. Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nat. Biotechnol. 21, 47–51 (2002).

    Article  Google Scholar 

  6. 6

    Dhar, S., Daniel, W. L., Giljohann, D. A., Mirkin, C. A. & Lippard, S. J. Polyvalent oligonucleotide gold nanoparticle conjugates as delivery vehicles for platinum(IV) warheads. J. Am. Chem. Soc. 131, 14652–14653 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Kam, N. W. S., O’Connell, M., Wisdom, J. A. & Dai, H. Carbon nanotubes as multifunctional biological transporters and near-infrared agents for selective cancer cell destruction. Proc. Natl Acad. Sci. USA 102, 11600–11605 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S. & Audet, J. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

    CAS  Article  Google Scholar 

  9. 9

    Zhang, C. et al. Pharmacokinetics, biodistribution, efficacy and safety of N-octyl-O-sulfate chitosan micelles loaded with paclitaxel. Biomaterials 29, 1233–1241 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Fonge, H., Huang, H., Scollard, D., Reilly, R. M. & Allen, C. Influence of formulation variables on the biodistribution of multifunctional block copolymer micelles. J. Control. Release 157, 366–374 (2012).

    CAS  Article  Google Scholar 

  11. 11

    Ye, L. et al. A pilot study in non-human primates shows no adverse response to intravenous injection of quantum dots. Nat. Nanotech. 7, 453–458 (2012).

    CAS  Article  Google Scholar 

  12. 12

    Fischer, H. C., Liu, L., Pang, K. S. & Chan, W. C. W. Pharmacokinetics of nanoscale quantum dots: in vivo distribution, sequestration, and clearance in the rat. Adv. Funct. Mater. 16, 1299–1305 (2006).

    CAS  Article  Google Scholar 

  13. 13

    Semmler-Behnke, M. et al. Biodistribution of 1.4- and 18-nm gold particles in rats. Small 4, 2108–2111 (2008).

    CAS  Article  Google Scholar 

  14. 14

    De Jong, W. H. et al. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 29, 1912–1919 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Liu, Z. et al. In vivo biodistribution and highly efficient tumour targeting of carbon nanotubes in mice. Nat. Nanotech. 2, 47–52 (2006).

    Article  Google Scholar 

  16. 16

    Yang, S. T. et al. Biodistribution of pristine single-walled carbon nanotubes in vivo. J. Phys. Chem. C 111, 17761–17764 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Hauck, T. S., Anderson, R. E., Fischer, H. C., Newbigging, S. & Chan, W. C. W. In vivo quantum-dot toxicity assessment. Small 6, 138–144 (2010).

    CAS  Article  Google Scholar 

  18. 18

    Kuwahira, I., Gonzalez, N. C., Heisler, N. & Piiper, J. Changes in regional blood flow distribution and oxygen supply during hypoxia in conscious rats. J. Appl. Physiol. 74, 211–214 (1993).

    CAS  Article  Google Scholar 

  19. 19

    Fournier, L. S. et al. Early modifications of hepatic perfusion measured by functional CT in a rat model of hepatocellular carcinoma using a blood pool contrast agent. Eur. Radiol. 14, 2125–2133 (2004).

    Article  Google Scholar 

  20. 20

    Miyazaki, S. et al. Investigation on the optimal position for the quantification of hepatic perfusion by use of dynamic contrast-enhanced computed tomography in rats. Radiol. Phys. Technol. 2, 183–188 (2009).

    Article  Google Scholar 

  21. 21

    Menger, M. D., Marzi, I. & Messmer, K. In vivo fluorescence microscopy for quantitative analysis of the hepatic microcirculation in hamsters and rats. Eur. Surg. Res. 23, 158–169 (1991).

    CAS  Article  Google Scholar 

  22. 22

    MacPhee, P. J., Schmidt, E. E. & Groom, A. C. Intermittence of blood flow in liver sinusoids, studied by high-resolution in vivo microscopy. Am. J. Physiol. Gastrointest. Liver Physiol. 269, G692–G698 (1995).

    CAS  Article  Google Scholar 

  23. 23

    Ingham, D. B. Diffusion of aerosols from a stream flowing through a cylindrical tube. J. Aerosol. Sci. 6, 125–132 (1975).

    Article  Google Scholar 

  24. 24

    Davies, C. N. Diffusion and sedimentation of aerosol particles from Poiseuille flow in pipes. J. Aerosol. Sci. 4, 317–328 (1973).

    Article  Google Scholar 

  25. 25

    Dobrovolskaia, M. A. & McNeil, S. E. Immunological properties of engineered nanomaterials. Nat. Nanotech. 2, 469–478 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Lunov, O. et al. Differential uptake of functionalized polystyrene nanoparticles by human macrophages and a monocytic cell line. ACS Nano 5, 1657–1669 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Wang, H., Wu, L. & Reinhard, B. M. Scavenger receptor mediated endocytosis of silver nanoparticles into J774A.1 macrophages is heterogeneous. ACS Nano 6, 7122–7132 (2012).

    CAS  Article  Google Scholar 

  28. 28

    Sykes, E. A., Chen, J., Zheng, G. & Chan, W. C. W. Investigating the impact of nanoparticle size on active and passive tumor targeting efficiency. ACS Nano 8, 5696–5706 (2014).

    CAS  Article  Google Scholar 

  29. 29

    Perrault, S. D., Walkey, C., Jennings, T., Fischer, H. C. & Chan, W. C. W. Mediating tumor targeting efficiency of nanoparticles through design. Nano Lett. 9, 1909–1915 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Cho, W.-S. et al. Size-dependent tissue kinetics of PEG-coated gold nanoparticles. Toxicol. Appl. Pharmacol. 245, 116–123 (2010).

    CAS  Article  Google Scholar 

  31. 31

    Chithrani, B. D. & Chan, W. C. W. Elucidating the mechanism of cellular uptake and removal of protein-coated gold nanoparticles of different sizes and shapes. Nano Lett. 7, 1542–1550 (2007).

    CAS  Article  Google Scholar 

  32. 32

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

    CAS  Article  Google Scholar 

  33. 33

    Cormode, D. P. et al. A versatile and tunable coating strategy allows control of nanocrystal delivery to cell types in the liver. Bioconjug. Chem. 22, 353–361 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Cheng, S.-H. et al. Visualizing dynamics of sub-hepatic distribution of nanoparticles using intravital multiphoton fluorescence microscopy. ACS Nano 6, 4122–4131 (2012).

    CAS  Article  Google Scholar 

  35. 35

    Akinc, A. et al. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms. Mol. Ther. 18, 1357–1364 (2010).

    CAS  Article  Google Scholar 

  36. 36

    Sadauskas, E. et al. Kupffer cells are central in the removal of nanoparticles from the organism. Part. Fibre Toxicol. 4, 10–17 (2007).

    Article  Google Scholar 

  37. 37

    Bartneck, M. et al. Peptide-functionalized gold nanorods increase liver injury in hepatitis. ACS Nano 6, 8767–8777 (2012).

    CAS  Article  Google Scholar 

  38. 38

    Nakashima, M. et al. Pivotal advance: characterization of mouse liver phagocytic B cells in innate immunity. J. Leukoc. Biol. 91, 537–546 (2012).

    CAS  Article  Google Scholar 

  39. 39

    Stock, R. J., Cilento, E. V., Reilly, F. D. & McCuskey, R. S. A compartmental analysis of the splenic circulation in rat. Am. J. Physiol. Heart Circ. Physiol. 245, H17–H21 (1983).

    CAS  Article  Google Scholar 

  40. 40

    Chadburn, A. The spleen: anatomy and anatomical function. Semin. Hematol. 37, 13–21 (2000).

    CAS  Article  Google Scholar 

  41. 41

    Delp, M. D., Evans, M. V. & Duan, C. Effects of aging on cardiac output, regional blood flow, and body composition in Fischer-344 rats. J. Appl. Physiol. 85, 1813–1822 (1998).

    CAS  Article  Google Scholar 

  42. 42

    Walkey, C. D., Olsen, J. B., Guo, H., Emili, A. & Chan, W. C. W. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 134, 2139–2147 (2012).

    CAS  Article  Google Scholar 

  43. 43

    Jones, S. W. et al. Nanoparticle clearance is governed by Th1/Th2 immunity and strain background. J. Clin. Invest. 123, 3061–3073 (2013).

    CAS  Article  Google Scholar 

  44. 44

    Koo, A., Liang, I. Y. & Cheng, K. K. Hepatic sinusoidal responses to intraportal injections of phenylephrine and isoprenaline in the rat. Clin. Exp. Pharmacol. Physiol. 3, 391–395 (1976).

    CAS  Article  Google Scholar 

  45. 45

    Hagemann, T. et al. ‘Re-educating’ tumor-associated macrophages by targeting NF-B. J. Exp. Med. 205, 1261–1268 (2008).

    CAS  Article  Google Scholar 

Download references


We would to acknowledge the Canadian Institute of Health Research, Natural Sciences and Engineering Research Council, and Collaborative Health Research Program for funding the project. K.M.T. thanks the NSERC Vanier Canada Graduate Scholarship Program and the Surgeon-Scientist Program at the University of Toronto for financial support. S.A.M. thanks the CASL/CIHR Hepatology Fellowship Program and the National CIHR Research Training Program in Hepatitis C for financial support. We would also like to acknowledge M. Peralta and C. Hoculada from the University Health Network Pathology Research Program (Toronto, Canada), D. Holmyard from the Mount Sinai Advanced Bioimaging Centre (Toronto, Canada), F. Xu from the University Health Network Advanced Optical Microscopy Facility (Toronto, Canada), D. White from the Department of Immunology, University of Toronto (Toronto, Ontario), J. Manual, J. Feld and V. Cherepanov from the Toronto Centre for Liver Disease (Toronto, Canada), J. Krieger from the SPARC Biocentre at the Hospital for Sick Children (Toronto, Canada) and A. Black from the Department of Anatomy, National University of Ireland, Galway (Galway, Ireland) for their assistance.

Author information




K.M.T., S.A.M., J.B.C., I.D.M. and W.C.W.C. conceived the idea. K.M.T., S.A.M., O.A.A., I.D.M. and W.C.W.C. analysed the data. K.M.T. and S.A.M. conducted the experiments with assistance from X.-Z.M., V.N.S., J.E., B.O., S.M.F., E.A.S., N.G. and J.M.K. A.Z. performed the mathematical modelling. B.A.A., M.S. and M.A.O. supervised some of the work.

Corresponding authors

Correspondence to Ian D. McGilvray or Warren C. W. Chan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 8315 kb)

Supplementary Movie 1

Supplementary Movie 1 (MP4 2858 kb)

Supplementary Movie 2

Supplementary Movie 2 (MP4 2499 kb)

Supplementary Information

Characterization of the protein corona (XLSX 46 kb)

Supplementary Information

Mathematica code (PDF 478 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tsoi, K., MacParland, S., Ma, XZ. et al. Mechanism of hard-nanomaterial clearance by the liver. Nature Mater 15, 1212–1221 (2016).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing