Skip to main content

Thank you for visiting nature.com. 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.

Obstacles and opportunities in a forward vision for cancer nanomedicine

Nature Materials volume 20, pages 1469–1479 (2021)Cite this article

Subjects

Abstract

Cancer nanomedicines were initially envisioned as magic bullets, travelling through the circulation to target tumours while sparing healthy tissues the toxicity of classic chemotherapy. While a limited number of nanomedicine therapies have resulted, the disappointing news is that major obstacles were overlooked in the nanoparticle’s journey. However, some of these challenges may be turned into opportunities. Here, we discuss biological barriers to cancer nanomedicines and elaborate on two directions that the field is currently exploring to meet its initial expectations. The first strategy entails re-engineering cancer nanomedicines to prevent undesired interactions en route to the tumour. The second aims instead to leverage these obstacles into out-of-the-box diagnostic and therapeutic applications of nanomedicines, for cancer and beyond. Both paths require, among other developments, a deeper understanding of nano–bio interactions. We offer a forward look at how classic cancer nanomedicine may overcome its limitations while contributing to other areas of research.

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

$39.95

Learn more

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

Fig. 1: Elapsed time from first clinical trial to FDA approval of cancer nanomedicines.
Fig. 2: Biological barriers to systemically administered nanomedicines with intracellular targets in cancer cells.
Fig. 3: Novel applications of cancer nanomedicines based on what have previously been considered undesired interactions with biological barriers.

References

  1. Nichols, J. W. & Bae, Y. H. EPR: evidence and fallacy. J. Control. Release 190, 451–464 (2014).

    Article  CAS  Google Scholar 

  2. Matsumura, Y. & Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 46, 6387–6392 (1986).

    CAS  Google Scholar 

  3. Gerlowski, L. E. & Jain, R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc. Res. 31, 288–305 (1986).

    Article  CAS  Google Scholar 

  4. Landgraf, M. et al. Targeted camptothecin delivery via silicon nanoparticles reduces breast cancer metastasis. Biomaterials 240, 119791 (2020).

    Article  CAS  Google Scholar 

  5. Chen, C. et al. Reversibly-regulated drug release using poly(tannic acid) fabricated nanocarriers for reduced secondary side effects in tumor therapy. Nanoscale Horiz. 5, 986–998 (2020).

    Article  CAS  Google Scholar 

  6. Al-Ahmady, Z. S., Chaloin, O. & Kostarelos, K. Monoclonal antibody-targeted, temperature-sensitive liposomes: in vivo tumor chemotherapeutics in combination with mild hyperthermia. J. Control. Release 196, 332–343 (2014).

    Article  CAS  Google Scholar 

  7. Davis, M. E. et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature 464, 1067–1070 (2010).

    Article  CAS  Google Scholar 

  8. Quintanilla, M. et al. Thermal monitoring during photothermia: hybrid probes for simultaneous plasmonic heating and near-infrared optical nanothermometry. Theranostics 9, 7298–7312 (2019).

    Article  CAS  Google Scholar 

  9. Feng, L., Gai, S., He, F., Yang, P. & Zhao, Y. Multifunctional bismuth ferrite nanocatalysts with optical and magnetic functions for ultrasound-enhanced tumor theranostics. ACS Nano 14, 7245–7258 (2020).

    Article  CAS  Google Scholar 

  10. Anselmo, A. C. & Mitragotri, S. Nanoparticles in the clinic: an update. Bioeng. Transl. Med. 4, e10143 (2019).

    Google Scholar 

  11. He, H., Liu, L., Morin, E. E., Liu, M. & Schwendeman, A. Survey of clinical translation of cancer nanomedicines—lessons learned from successes and failures. Acc. Chem. Res. 52, 2445–2461 (2019).

    Article  CAS  Google Scholar 

  12. Shi, J., Kantoff, P. W., Wooster, R. & Farokhzad, O. C. Cancer nanomedicine: progress, challenges and opportunities. Nat. Rev. Cancer 17, 20–37 (2017).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Sindhwani, S. et al. The entry of nanoparticles into solid tumours. Nat. Mater. 19, 566–575 (2020).

    Article  CAS  Google Scholar 

  15. Sofias, A. M. et al. Tumor targeting by αvβ3-integrin-specific lipid nanoparticles occurs via phagocyte hitchhiking. ACS Nano 14, 7832–7846 (2020).

    Article  CAS  Google Scholar 

  16. Salvati, A. et al. Transferrin-functionalized nanoparticles lose their targeting capabilities when a biomolecule corona adsorbs on the surface. Nat. Nanotechnol. 8, 137–143 (2013).

    Article  CAS  Google Scholar 

  17. Lazarovits, J., Chen, Y. Y., Sykes, E. A. & Chan, W. C. Nanoparticle–blood interactions: the implications on solid tumour targeting. Chem. Commun. 51, 2756–2767 (2015).

    Article  CAS  Google Scholar 

  18. Chen, F. et al. Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nat. Nanotechnol. 12, 387–393 (2017).

    Article  CAS  Google Scholar 

  19. Ju, Y. et al. Person-specific biomolecular coronas modulate nanoparticle interactions with immune cells in human blood. ACS Nano 14, 15723–15737 (2020).

    Article  CAS  Google Scholar 

  20. Shah, N. B. et al. Blood–nanoparticle interactions and in vivo biodistribution: impact of surface PEG and ligand properties. Mol. Pharm. 9, 2146–2155 (2012).

    Article  CAS  Google Scholar 

  21. Campbell, F. et al. Directing nanoparticle biodistribution through evasion and exploitation of stab2-dependent nanoparticle uptake. ACS Nano 12, 2138–2150 (2018).

    Article  CAS  Google Scholar 

  22. Hayashi, Y. et al. Differential nanoparticle sequestration by macrophages and scavenger endothelial cells visualized in vivo in real-time and at ultrastructural resolution. ACS Nano 14, 1665–1681 (2020).

    Article  CAS  Google Scholar 

  23. Balasubramanian, S. K. et al. Biodistribution of gold nanoparticles and gene expression changes in the liver and spleen after intravenous administration in rats. Biomaterials 31, 2034–2042 (2010).

    Article  CAS  Google Scholar 

  24. Miao, L. & Huang, L. Exploring the tumor microenvironment with nanoparticles. Cancer Treat. Res. 166, 193–226 (2015).

    Article  CAS  Google Scholar 

  25. Hansen, A. E. et al. Positron emission tomography based elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano 9, 6985–6995 (2015).

    Article  CAS  Google Scholar 

  26. de Lazaro, I. & Mooney, D. J. A nanoparticle’s pathway into tumours. Nat. Mater. 19, 486–487 (2020).

    Article  CAS  Google Scholar 

  27. Weniger, M., Honselmann, K. C. & Liss, A. S. The extracellular matrix and pancreatic cancer: a complex relationship. Cancers 10, 316 (2018).

    Article  CAS  Google Scholar 

  28. Lee, H., Fonge, H., Hoang, B., Reilly, R. M. & Allen, C. The effects of particle size and molecular targeting on the intratumoral and subcellular distribution of polymeric nanoparticles. Mol. Pharm. 7, 1195–1208 (2010).

    Article  CAS  Google Scholar 

  29. Chauhan, V. P. et al. Fluorescent nanorods and nanospheres for real-time in vivo probing of nanoparticle shape-dependent tumor penetration. Angew. Chem. Int. Ed. 50, 11417–11420 (2011).

    Article  CAS  Google Scholar 

  30. Stylianopoulos, T. et al. Diffusion of particles in the extracellular matrix: the effect of repulsive electrostatic interactions. Biophys. J. 99, 1342–1349 (2010).

    Article  CAS  Google Scholar 

  31. Miller, M. A. et al. Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(iv) pro-drug. Nat. Commun. 6, 8692 (2015).

    Article  CAS  Google Scholar 

  32. Korangath, P. et al. Nanoparticle interactions with immune cells dominate tumor retention and induce T cell-mediated tumor suppression in models of breast cancer. Sci. Adv. 6, eaay1601 (2020).

    Article  CAS  Google Scholar 

  33. Donahue, N. D., Acar, H. & Wilhelm, S. Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine. Adv. Drug Deliv. Rev. 143, 68–96 (2019).

    Article  CAS  Google Scholar 

  34. de Lazaro, I. et al. Graphene oxide as a 2D platform for complexation and intracellular delivery of siRNA. Nanoscale 11, 13863–13877 (2019).

    Article  Google Scholar 

  35. Price, L. S. L., Stern, S. T., Deal, A. M., Kabanov, A. V. & Zamboni, W. C. A reanalysis of nanoparticle tumor delivery using classical pharmacokinetic metrics. Sci. Adv. 6, eaay9249 (2020).

    Article  CAS  Google Scholar 

  36. Park, K. The beginning of the end of the nanomedicine hype. J. Control. Release 305, 221–222 (2019).

    Article  CAS  Google Scholar 

  37. Huang, S. K. et al. Extravasation and transcytosis of liposomes in Kaposi’s sarcoma-like dermal lesions of transgenic mice bearing the HIV tat gene. Am. J. Pathol. 143, 10–14 (1993).

    CAS  Google Scholar 

  38. Liu, X., Jiang, J. & Meng, H. Transcytosis—an effective targeting strategy that is complementary to ‘EPR effect’ for pancreatic cancer nano drug delivery. Theranostics 9, 8018–8025 (2019).

    Article  CAS  Google Scholar 

  39. Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).

    Article  CAS  Google Scholar 

  40. Liu, X. et al. Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer. J. Clin. Invest. 127, 2007–2018 (2017).

    Article  Google Scholar 

  41. Huo, D., Jiang, X. & Hu, Y. Recent advances in nanostrategies capable of overcoming biological barriers for tumor management. Adv. Mater. 32, e1904337 (2020).

    Google Scholar 

  42. Blanco, E., Shen, H. & Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 33, 941–951 (2015).

    Article  CAS  Google Scholar 

  43. Jin, Q., Deng, Y., Chen, X. & Ji, J. Rational design of cancer nanomedicine for simultaneous stealth surface and enhanced cellular uptake. ACS Nano 13, 954–977 (2019).

    CAS  Google Scholar 

  44. Hama, S. et al. Overcoming the polyethylene glycol dilemma via pathological environment-sensitive change of the surface property of nanoparticles for cellular entry. J. Control. Release 206, 67–74 (2015).

    Article  CAS  Google Scholar 

  45. Hatakeyama, H. et al. Development of a novel systemic gene delivery system for cancer therapy with a tumor-specific cleavable PEG-lipid. Gene Ther. 14, 68–77 (2007).

    Article  CAS  Google Scholar 

  46. Ouyang, B. et al. The dose threshold for nanoparticle tumour delivery. Nat. Mater. 19, 1362–1371 (2020).

    Article  CAS  Google Scholar 

  47. Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7, 383–388 (2012).

    Article  CAS  Google Scholar 

  48. Meng, H. et al. Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice. ACS Nano 7, 10048–10065 (2013).

    Article  CAS  Google Scholar 

  49. Seki, T. et al. Tumour necrosis factor-alpha increases extravasation of virus particles into tumour tissue by activating the Rho A/Rho kinase pathway. J. Control. Release 156, 381–389 (2011).

    Article  CAS  Google Scholar 

  50. Bai, X. et al. Toward a systematic exploration of nano–bio interactions. Toxicol. Appl. Pharmacol. 323, 66–73 (2017).

    Article  CAS  Google Scholar 

  51. Walkey, C. D. et al. Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. ACS Nano 8, 2439–2455 (2014).

    Article  CAS  Google Scholar 

  52. Lazarovits, J. et al. Supervised learning and mass spectrometry predicts the in vivo fate of nanomaterials. ACS Nano 13, 8023–8034 (2019).

    Article  CAS  Google Scholar 

  53. Yaari, Z. et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nat. Commun. 7, 13325 (2016).

    Article  CAS  Google Scholar 

  54. Paunovska, K. et al. A direct comparison of in vitro and in vivo nucleic acid delivery mediated by hundreds of nanoparticles reveals a weak correlation. Nano Lett. 18, 2148–2157 (2018).

    Article  CAS  Google Scholar 

  55. Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1, 0029 (2017).

    Article  CAS  Google Scholar 

  56. Hadjidemetriou, M. et al. The human in vivo biomolecule corona onto pegylated liposomes: a proof-of-concept clinical study. Adv. Mater. 31, e1803335 (2019).

    Article  CAS  Google Scholar 

  57. Papafilippou, L., Claxton, A., Dark, P., Kostarelos, K. & Hadjidemetriou, M. Protein corona fingerprinting to differentiate sepsis from non-infectious systemic inflammation. Nanoscale 12, 10240–10253 (2020).

    Article  CAS  Google Scholar 

  58. Blume, J. E. et al. Rapid, deep and precise profiling of the plasma proteome with multi-nanoparticle protein corona. Nat. Commun. 11, 3662 (2020).

    Article  CAS  Google Scholar 

  59. Corbo, C. et al. Analysis of the human plasma proteome using multi-nanoparticle protein corona for detection of Alzheimer’s disease. Adv. Health. Mater. 10, e2000948 (2021).

    Article  CAS  Google Scholar 

  60. Ren, J. et al. Precision nanomedicine development based on specific opsonization of human cancer patient-personalized protein coronas. Nano Lett. 19, 4692–4701 (2019).

    Article  CAS  Google Scholar 

  61. Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat. Nanotechnol. 12, 877–882 (2017).

    Article  CAS  Google Scholar 

  62. Wang, M. et al. NIR-triggered phototherapy and immunotherapy via an antigen-capturing nanoplatform for metastatic cancer treatment. Adv. Sci. 6, 1802157 (2019).

    Article  CAS  Google Scholar 

  63. Lazarovits, J. et al. Synthesis of patient-specific nanomaterials. Nano Lett. 19, 116–123 (2019).

    Article  CAS  Google Scholar 

  64. Smith, B. R. et al. Selective uptake of single-walled carbon nanotubes by circulating monocytes for enhanced tumour delivery. Nat. Nanotechnol. 9, 481–487 (2014).

    Article  CAS  Google Scholar 

  65. Chu, D., Dong, X., Zhao, Q., Gu, J. & Wang, Z. Photosensitization priming of tumor microenvironments improves delivery of nanotherapeutics via neutrophil infiltration. Adv. Mater. 29, 1701021 (2017).

    Article  CAS  Google Scholar 

  66. Chu, D., Gao, J. & Wang, Z. Neutrophil-mediated delivery of therapeutic nanoparticles across blood vessel barrier for treatment of inflammation and infection. ACS Nano 9, 11800–11811 (2015).

    Article  CAS  Google Scholar 

  67. Irvine, D. J. & Dane, E. L. Enhancing cancer immunotherapy with nanomedicine. Nat. Rev. Immunol. 20, 321–334 (2020).

    Article  CAS  Google Scholar 

  68. Getts, D. R. et al. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nat. Biotechnol. 30, 1217–1224 (2012).

    Article  CAS  Google Scholar 

  69. Liu, Q. et al. Use of polymeric nanoparticle platform targeting the liver to induce Treg-mediated antigen-specific immune tolerance in a pulmonary allergen sensitization model. ACS Nano 13, 4778–4794 (2019).

    Article  CAS  Google Scholar 

  70. Yeste, A., Nadeau, M., Burns, E. J., Weiner, H. L. & Quintana, F. J. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 109, 11270–11275 (2012).

    Article  CAS  Google Scholar 

  71. Rodell, C. B. et al. Tlr7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018).

    Article  CAS  Google Scholar 

  72. Qian, Y. et al. Molecular-targeted immunotherapeutic strategy for melanoma via dual-targeting nanoparticles delivering small interfering RNA to tumor-associated macrophages. ACS Nano 11, 9536–9549 (2017).

    Article  CAS  Google Scholar 

  73. de Lázaro, I. et al. Deep tissue translocation of graphene oxide sheets in human glioblastoma 3D spheroids and an orthotopic xenograft model. Adv. Ther. 4, 2000109 (2021).

    Article  CAS  Google Scholar 

  74. Swierczewska, M., Kozlov, S. & Adiseshaiah, P. P. in Oncogenomics (eds Dammacco, F. & Silvestris, F.) 313–327 (Academic, 2019).

  75. Landgraf, M., McGovern, J. A., Friedl, P. & Hutmacher, D. W. Rational design of mouse models for cancer research. Trends Biotechnol. 36, 242–251 (2018).

    Article  CAS  Google Scholar 

  76. Carvalho, M. R. et al. Colorectal tumor-on-a-chip system: a 3D tool for precision onco-nanomedicine. Sci. Adv. 5, eaaw1317 (2019).

    Article  CAS  Google Scholar 

  77. Albanese, A., Lam, A. K., Sykes, E. A., Rocheleau, J. V. & Chan, W. C. Tumour-on-a-chip provides an optical window into nanoparticle tissue transport. Nat. Commun. 4, 2718 (2013).

    Article  CAS  Google Scholar 

  78. Wang, H. F. et al. Tumor-vasculature-on-a-chip for investigating nanoparticle extravasation and tumor accumulation. ACS Nano 12, 11600–11609 (2018).

    Article  CAS  Google Scholar 

  79. Chen, Y. Y., Syed, A. M., MacMillan, P., Rocheleau, J. V. & Chan, W. C. W. Flow rate affects nanoparticle uptake into endothelial cells. Adv. Mater. 32, e1906274 (2020).

    Article  CAS  Google Scholar 

  80. Faria, M. et al. Minimum information reporting in bio–nano experimental literature. Nat. Nanotechnol. 13, 777–785 (2018).

    Article  CAS  Google Scholar 

  81. Leong, H. S. et al. On the issue of transparency and reproducibility in nanomedicine. Nat. Nanotechnol. 14, 629–635 (2019).

    Article  CAS  Google Scholar 

  82. Bustin, S. & Nolan, T. Talking the talk, but not walking the walk: RT-qPCR as a paradigm for the lack of reproducibility in molecular research. Eur. J. Clin. Invest. 47, 756–774 (2017).

    Article  Google Scholar 

  83. van der Meel, R. et al. Smart cancer nanomedicine. Nat. Nanotechnol. 14, 1007–1017 (2019).

    Article  CAS  Google Scholar 

  84. Judson, I. et al. Randomised phase II trial of pegylated liposomal doxorubicin (DOXIL®/CAELYX®) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur. J. Cancer 37, 870–877 (2001).

    Article  CAS  Google Scholar 

  85. Rifkin, R. M., Gregory, S. A., Mohrbacher, A. & Hussein, M. A. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma. Cancer 106, 848–858 (2006).

    Article  CAS  Google Scholar 

  86. Xing, M., Yan, F., Yu, S. & Shen, P. Efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy in advanced breast cancer: a meta-analysis of ten randomized controlled trials. PLoS ONE 10, e0133569–e0133569 (2015).

    Article  CAS  Google Scholar 

  87. Xu, X. et al. Clinical comparison between paclitaxel liposome (Lipusu®) and paclitaxel for treatment of patients with metastatic gastric cancer. Asian Pac. J. Cancer Prev. 14, 2591–2594 (2013).

    Article  Google Scholar 

  88. Tossey, J. C. et al. Comparison of conventional versus liposomal irinotecan in combination with fluorouracil for advanced pancreatic cancer: a single-institution experience. Med. Oncol. 36, 87 (2019).

    Article  CAS  Google Scholar 

  89. Kang, Y. K. et al. Efficacy and safety findings from DREAM: a phase III study of DHP107 (oral paclitaxel) versus i.v. paclitaxel in patients with advanced gastric cancer after failure of first-line chemotherapy. Ann. Oncol. 29, 1220–1226 (2018).

    Article  Google Scholar 

  90. Van Norman, G. A. Drugs, devices, and the FDA: Part 1: An overview of approval processes for drugs. JACC Basic Transl. Sci. 1, 170–179 (2016).

    Article  Google Scholar 

Download references

Acknowledgements

We acknowledge funding from the National Cancer Institute of the National Institutes of Health under award numbers U01CA214369 and U54CA244726. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We apologize to colleagues whose relevant publications were not cited due to space limitations.

Author information

Authors and Affiliations

  1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Irene de Lázaro & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA, USA

    Irene de Lázaro & David J. Mooney

Authors
  1. Irene de Lázaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David J. Mooney
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.d.L. and D.J.M. conceived and wrote the manuscript.

Corresponding author

Correspondence to David J. Mooney.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Materials thanks Shuming Nie and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

de Lázaro, I., Mooney, D.J. Obstacles and opportunities in a forward vision for cancer nanomedicine. Nat. Mater. 20, 1469–1479 (2021). https://doi.org/10.1038/s41563-021-01047-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41563-021-01047-7

This article is cited by

Search

Advanced search

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