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.

Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth


The design of cancer-targeting particles with precisely tuned physicochemical properties may enhance the delivery of therapeutics and access to pharmacological targets. However, a molecular-level understanding of the interactions driving the fate of nanomedicine in biological systems remains elusive. Here, we show that ultrasmall (<10 nm in diameter) poly(ethylene glycol)-coated silica nanoparticles, functionalized with melanoma-targeting peptides, can induce a form of programmed cell death known as ferroptosis in starved cancer cells and cancer-bearing mice. Tumour xenografts in mice intravenously injected with nanoparticles using a high-dose multiple injection scheme exhibit reduced growth or regression, in a manner that is reversed by the pharmacological inhibitor of ferroptosis, liproxstatin-1. These data demonstrate that ferroptosis can be targeted by ultrasmall silica nanoparticles and may have therapeutic potential.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


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

Figure 1: αMSH-PEG-C′-dot particles and their localization to lysosomal networks.
Figure 2: αMSH-PEG-C′ dot particles induce cell death in amino-acid-deprived conditions.
Figure 3: αMSH-PEG-C′ dot particle-induced cell death is not apoptosis, necroptosis or autosis.
Figure 4: Ferroptosis is the underlying mechanisms of αMSH particle-induced cell death.
Figure 5: αMSH-PEG-C′ dots induce cell death in different types of cancer cells.
Figure 6: αMSH-PEG-C′ dots inhibit tumour growth in 786-O and HT-1080 xenograft models.


  1. Davis, M. E., Chen, Z. G. & Shin, D. M. Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7, 771–782 (2008).

    Article  CAS  Google Scholar 

  2. Phillips, E. et al. Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Sci. Transl. Med. 6, 260ra149 (2014).

    Article  Google Scholar 

  3. Duncan, R. & Richardson, S. C. Endocytosis and intracellular trafficking as gateways for nanomedicine delivery: opportunities and challenges. Mol. Pharmacol. 9, 2380–2402 (2012).

    Article  CAS  Google Scholar 

  4. Duncan, R. & Gaspar, R. Nanomedicine(s) under the microscope. Mol. Pharmacol. 8, 2101–2141 (2011).

    Article  CAS  Google Scholar 

  5. Ma, X. et al. Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment. ACS Nano 5, 8629–8639 (2011).

    Article  CAS  Google Scholar 

  6. Li, J. J., Hartono, D., Ong, C. N., Bay, B. H. & Yung, L. Y. Autophagy and oxidative stress associated with gold nanoparticles. Biomaterials 31, 5996–6003 (2010).

    Article  CAS  Google Scholar 

  7. Chen, N. et al. Long-term effects of nanoparticles on nutrition and metabolism. Small 10, 3603–3611 (2014).

    Article  CAS  Google Scholar 

  8. Li, C. et al. PAMAM nanoparticles promote acute lung injury by inducing autophagic cell death through the Akt-TSC2-mTOR signaling pathway. J. Mol. Cell Biol. 1, 37–45 (2009).

    Article  CAS  Google Scholar 

  9. Stern, S. T., Adiseshaiah, P. P. & Crist, R. M. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Part. Fibre Toxicol. 9, 20 (2012).

    Article  CAS  Google Scholar 

  10. Ma, K. et al. Control of ultrasmall sub-10 nm ligand-functionalized fluorescent core–shell silica nanoparticle growth in water. Chem. Mater. 27, 4119–4133 (2015).

    Article  CAS  Google Scholar 

  11. Bradbury, M. S. et al. Clinically-translated silica nanoparticles as dual-modality cancer-targeted probes for image-guided surgery and interventions. Integr. Biol. (Camb.) 5, 74–86 (2013).

    Article  CAS  Google Scholar 

  12. Benezra, M. et al. Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma. J. Clin. Invest. 121, 2768–2780 (2011).

    Article  CAS  Google Scholar 

  13. Yoo, B. et al. Ultrasmall dual-modality silica nanoparticle drug conjugates: design, synthesis, and characterization. Bioorg. Med. Chem. 23, 7119–7130 (2015).

    Article  CAS  Google Scholar 

  14. Miao, Y., Benwell, K. & Quinn, T. P. 99mTc- and 111In-labeled alpha-melanocyte-stimulating hormone peptides as imaging probes for primary and pulmonary metastatic melanoma detection. J. Nucl. Med. 48, 73–80 (2007).

    CAS  Google Scholar 

  15. Mizushima, N., Yoshimori, T. & Levine, B. Methods in mammalian autophagy research. Cell 140, 313–326 (2010).

    Article  CAS  Google Scholar 

  16. Nelson, D. A. et al. Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Dev. 18, 2095–2107 (2004).

    Article  CAS  Google Scholar 

  17. Kandasamy, K. et al. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res. 63, 1712–1721 (2003).

    CAS  Google Scholar 

  18. Jacobson, M. D. et al. Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 361, 365–369 (1993).

    Article  CAS  Google Scholar 

  19. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100–1111 (2009).

    Article  CAS  Google Scholar 

  20. Liu, Y. et al. Autosis is a Na+, K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc. Natl Acad. Sci. USA 110, 20364–20371 (2013).

    Article  CAS  Google Scholar 

  21. Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    Article  CAS  Google Scholar 

  22. Linkermann, A. et al. Synchronized renal tubular cell death involves ferroptosis. Proc. Natl Acad. Sci. USA 111, 16836–16841 (2014).

    Article  CAS  Google Scholar 

  23. Ruhrberg, C. & De Palma, M. A double agent in cancer: deciphering macrophage roles in human tumors. Nat. Med. 16, 861–862 (2010).

    Article  CAS  Google Scholar 

  24. Guiducci, C., Vicari, A. P., Sangaletti, S., Trinchieri, G. & Colombo, M. P. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65, 3437–3446 (2005).

    Article  CAS  Google Scholar 

  25. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

    Article  CAS  Google Scholar 

  26. Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    Article  CAS  Google Scholar 

  27. Friedmann Angeli, J. P. et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol. 16, 1180–1191 (2014).

    Article  CAS  Google Scholar 

  28. Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).

    Article  CAS  Google Scholar 

  29. Gabizon, A. et al. Cancer nanomedicines: closing the translational gap. Lancet 384, 2175–2176 (2014).

    Article  Google Scholar 

  30. Ma, K., Zhang, D., Cong, Y. & Wiesner, U. Elucidating the mechanism of silica nanoparticle PEGylation processes using fluorescence correlation spectroscopies. Chem. Mater. 28, 1537–1545 (2016).

    Article  CAS  Google Scholar 

  31. Roveri, A., Maiorino, M. & Ursini, F. Enzymatic and immunological measurements of soluble and membrane-bound phospholipid-hydroperoxide glutathione peroxidase. Methods Enzymol. 233, 202–212 (1994).

    Article  CAS  Google Scholar 

  32. Zeger, S. L., Liang, K. Y. & Albert, P. S. Models for longitudinal data: a generalized estimating equation approach. Biometrics 44, 1049–1060 (1988).

    Article  CAS  Google Scholar 

Download references


This study was funded by grants from the National Institutes of Health (R01GM111350 to M.O.; 1R01CA161280-01A1 to M.B. and U.W.; 1U54 CA199081-01 to M.B. and U.W.; R01GM113013 and R01CA166413 to X.J.; Sloan Kettering Institute Core Grant P30 CA008748CCSG and the Benjamin Friedman Research Fund to M.O.). Peptide synthesis was conducted by the University of Missouri Structural Biology Core.

Author information

Authors and Affiliations



Product preparation was performed by K.M., T.Q. and M.Z.T., experimental design by S.E.K., M.O., M.S.B., K.M., L.Z., M.Go., X.J., P.Z., S.M., F.C., T.Q. and U.W., data acquisition by S.E.K., L.Z., K.M., M.Z.T., M.Go., X.J., M.P., F.C., S.M., M.S.B., M.O., I.I., M.C. and M.R., data analysis and interpretation by S.E.K., M.O., M.S.B., K.M., M.P., F.C., P.Z., M.Ga., S.M., L.Z., U.W., I.I., M.C. and M.R., and preparation of the manuscript by S.E.K., M.O., M.S.B., M.Go., P.Z., K.M., S.M., T.Q. and U.W. All authors discussed the results and implications and commented on the manuscript.

Corresponding authors

Correspondence to Michelle S. Bradbury or Michael Overholtzer.

Ethics declarations

Competing interests

The authors have filed an international patent application PCT/US16/34351.

Supplementary information

Supplementary information

Supplementary information (PDF 4037 kb)

Supplementary Movie 1

Supplementary Movie 1 (MOV 1968 kb)

Supplementary Movie 2

Supplementary Movie 2 (MOV 3107 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, S., Zhang, L., Ma, K. et al. Ultrasmall nanoparticles induce ferroptosis in nutrient-deprived cancer cells and suppress tumour growth. Nature Nanotech 11, 977–985 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

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