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.

  • Review Article
  • Published:

The mechanisms of nanoparticle delivery to solid tumours

Nature Reviews Bioengineering volume 2, pages 201–213 (2024)Cite this article

Subjects

Abstract

Nanoparticles for the detection and treatment of cancer have suffered from limited clinical translation. A key problem has been the lack of understanding of the mechanisms of nanoparticle delivery to solid tumours. The current delivery mechanism is called the enhanced permeability and retention effect, which states that nanoparticles passively enter the tumour through gaps between endothelial cells and are retained because of poor lymphatic drainage. However, nanoparticles designed according to the enhanced permeability and retention effect have limited delivery to solid tumours. An alternative mechanism proposes that nanoparticles enter the tumour through active endothelial transport processes, are retained in the tumour due to interactions with tumour components and exit the tumour through lymphatic vessels. This mechanism is called the active transport and retention principle. In this Review, we explore the contrasting views of these two mechanisms of nanoparticle delivery to solid tumours, explaining the underlying biological mechanisms and their effect on nanoparticle design for cancer applications. Defining the nanoparticle delivery mechanisms to solid tumours is crucial to the advancement and clinical translation of cancer nanomedicines and to determining how nanoparticles should be engineered for medical use.

Key points

  • Nanoparticles can carry imaging agents and therapeutics for the detection and treatment of cancer and need to be delivered to the tumour at a high enough dose to be medically useful.

  • The enhanced permeability and retention (EPR) effect states that nanoparticle delivery to tumours is caused by interendothelial gaps in the vasculature and dysfunctional lymphatic vessels, and has long guided the design of cancer nanomedicines.

  • Nanoparticles often fail in clinical trials for cancer treatment, likely due to a lack of mechanistic understanding of the delivery process.

  • The EPR effect is insufficient to explain nanoparticle delivery into solid tumours.

  • The active transport and retention principle challenges the EPR effect, proposing active nanoparticle entry, retention and exit mechanisms as underlying nanoparticle delivery to solid tumours.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Timeline of the mechanisms of nanoparticle delivery to solid tumours.
Fig. 2: EPR mechanism of nanoparticle delivery.
Fig. 3: ATR mechanism of nanoparticle delivery.
Fig. 4: The delivery journey of cancer nanomedicine.

Similar content being viewed by others

References

  1. Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016). This article reports that a low amount of nanoparticles (0.7% injected dose) are delivered to solid tumours.

    Article  ADS  CAS  Google Scholar 

  2. Papahadjopoulos, D. & Miller, N. Phospholipid model membranes. I. Structural characteristics of hydrated liquid crystals. Biochim. Biophys. Acta Biomembr. 135, 624–638 (1967).

    Article  CAS  Google Scholar 

  3. Sessa, G. & Weissmann, G. Phospholipid spherules (liposomes) as a model for biological membranes. J. Lipid Res. 9, 310–318 (1968).

    Article  CAS  PubMed  Google Scholar 

  4. Dong, J. et al. EGFR aptamer-conjugated liposome-polycation-DNA complex for targeted delivery of SATB1 small interfering RNA to choriocarcinoma cells. Biomed. Pharmacother. 107, 849–859 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Kim, D., Jeong, Y. Y. & Jon, S. A drug-loaded aptamer−gold nanoparticle bioconjugate for combined CT imaging and therapy of prostate cancer. ACS Nano 4, 3689–3696 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Corsi, F. et al. HER2 expression in breast cancer cells is downregulated upon active targeting by antibody-engineered multifunctional nanoparticles in mice. ACS Nano 5, 6383–6393 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Cohen, H. et al. Sustained delivery and expression of DNA encapsulated in polymeric nanoparticles. Gene Ther. 7, 1896–1905 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Perez, C. et al. Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA. J. Control. Release 75, 211–224 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Levine, R. M., Pearce, T. R., Adil, M. & Kokkoli, E. Preparation and characterization of liposome-encapsulated plasmid DNA for gene delivery. Langmuir 29, 9208–9215 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Mai, Y. et al. Intranasal delivery of cationic liposome-protamine complex mRNA vaccine elicits effective anti-tumor immunity. Cell Immunol. 354, 104143 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. McKay, P. F. et al. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat. Commun. 11, 3523 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ashley, C. E. et al. Delivery of small interfering RNA by peptide-targeted mesoporous silica nanoparticle-supported lipid bilayers. ACS Nano 6, 2174–2188 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zinger, A. et al. Collagenase nanoparticles enhance the penetration of drugs into pancreatic tumors. ACS Nano 13, 11008–11021 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Feczkó, T., Tóth, J., Dósa, G. & Gyenis, J. Optimization of protein encapsulation in PLGA nanoparticles. Chem. Eng. Process Process Intensif. 50, 757–765 (2011).

    Article  Google Scholar 

  15. Cao, A. et al. A facile method to encapsulate proteins in silica nanoparticles: encapsulated green fluorescent protein as a robust fluorescence probe. Angew. Chem. 122, 3086–3089 (2010).

    Article  ADS  Google Scholar 

  16. George, T. A. et al. Liposome-encapsulated anthraquinone improves efficacy and safety in triple negative breast cancer. J. Control. Release 342, 31–43 (2022).

    Article  CAS  PubMed  Google Scholar 

  17. Ngo, W. et al. DNA-controlled encapsulation of small molecules in protein nanoparticles. J. Am. Chem. Soc. 142, 17938–17943 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Yoo, H. S., Lee, K. H., Oh, J. E. & Park, T. G. In vitro and in vivo anti-tumor activities of nanoparticles based on doxorubicin–PLGA conjugates. J. Control. Release 68, 419–431 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Rayamajhi, S. et al. pH-responsive cationic liposome for endosomal escape mediated drug delivery. Colloids Surf. B Biointerfaces 188, 110804 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. Palanikumar, L. et al. pH-responsive high stability polymeric nanoparticles for targeted delivery of anticancer therapeutics. Commun. Biol. 3, 95 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tai, L.-A. et al. Thermosensitive liposomes entrapping iron oxide nanoparticles for controllable drug release. Nanotechnology 20, 135101 (2009).

    Article  ADS  PubMed  Google Scholar 

  22. Sun, J., Yu, Z., Hong, C. & Pan, C. Biocompatible zwitterionic sulfobetaine copolymer‐coated mesoporous silica nanoparticles for temperature‐responsive drug release. Macromol. Rapid Commun. 33, 811–818 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Vlasova, K. Y. et al. Magnetic liposome design for drug release systems responsive to super-low frequency alternating current magnetic field (AC MF). J. Colloid Interf. Sci. 552, 689–700 (2019).

    Article  ADS  CAS  Google Scholar 

  24. Ge, J., Neofytou, E., Cahill, T. J., Beygui, R. E. & Zare, R. N. Drug release from electric-field-responsive nanoparticles. ACS Nano 6, 227–233 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Chauhan, V. P. & Jain, R. K. Strategies for advancing cancer nanomedicine. Nat. Mater. 12, 958–962 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2, 751–760 (2007). This review describes the EPR effect, that is, a passive mechanism of nanoparticle accumulation in tumours and retention due to dysfunctional tumour lymphatics.

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Nakamura, H., Fang, J., Jun, F. & Maeda, H. Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls. Expert Opin. Drug Deliv. 12, 53–64 (2014).

    Article  PubMed  Google Scholar 

  28. Lammers, T., Kiessling, F., Hennink, W. E. & Storm, G. Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress. J. Control. Release 161, 175–187 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. 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). This article established the accumulation and retention of macromolecules in solid tumours, linking these observations to tumour blood vascular leakiness and poor lymphatic drainage, providing the foundation of the EPR effect.

    CAS  PubMed  Google Scholar 

  30. 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). This review analyses nanomedicines in clinical trials, and describes the reasons for their success and failure.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Danhier, F. To exploit the tumor microenvironment: since the EPR effect fails in the clinic, what is the future of nanomedicine? J. Control. Release 244, 108–121 (2016).

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura, Y., Mochida, A., Choyke, P. L. & Kobayashi, H. Nanodrug delivery: is the enhanced permeability and retention effect sufficient for curing cancer? Bioconjug. Chem. 27, 2225–2238 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Park, K. The drug delivery field at the inflection point: time to fight its way out of the egg. J. Control. Release 267, 2–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Sun, D., Zhou, S. & Gao, W. What went wrong with anticancer nanomedicine design and how to make it right. ACS Nano 14, 12281–12290 (2020).

    Article  CAS  PubMed  Google Scholar 

  36. Weil, R. Chemotherapeutic experiments on rat tumors. J. Cancer Res. https://doi.org/10.1158/jcr.1916.95 (1916).

    Article  Google Scholar 

  37. Duran-Reynals, F. Studies on the localization of dyes and foreign proteins in normal and malignant tissues. Am. J. Cancer 3, 98–107 (1939).

    Google Scholar 

  38. Peterson, H.-I. & Appelgren, K. L. Experimental studies on the uptake and retention of labelled proteins in a rat tumour. Eur. J. Cancer 9, 543–547 (1973).

    Article  CAS  Google Scholar 

  39. Song, C. W. & Levitt, S. H. Quantitative study of vascularity in Walker carcinoma 256. Cancer Res. 31, 587–589 (1971).

    CAS  PubMed  Google Scholar 

  40. Wright, R. L. Vascular permeability in experimental brain tumors. Angiology 18, 69–75 (1967).

    Article  CAS  PubMed  Google Scholar 

  41. Gordon, R. T., Hines, J. R. & Gordon, D. Intracellular hyperthermia a biophysical approach to cancer treatment via intracellular temperature and biophysical alterations. Med. Hypotheses 5, 83–102 (1979).

    Article  CAS  PubMed  Google Scholar 

  42. Larson, S. M. Mechanisms of localization of gallium-67 in tumors. Semin. Nucl. Med. 8, 193–203 (1978).

    Article  CAS  PubMed  Google Scholar 

  43. Som, P. et al. 97Ru-transferrin uptake in tumor and abscess. Eur. J. Nucl. Med. 8, 491–494 (1983).

    Article  CAS  PubMed  Google Scholar 

  44. O’Connor, S. W. & Bale, W. F. Accessibility of circulating immunoglobulin G to the extravascular compartment of solid rat tumors. Cancer Res. 44, 3719–3723 (1984).

    PubMed  Google Scholar 

  45. Dvorak, H. F., Harvey, V. S. & McDonagh, J. Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res. 44, 3348–3354 (1984).

    CAS  PubMed  Google Scholar 

  46. L’Abbé, M. R., Fischer, P. W. F., Trick, K. D. & Chavez, E. R. Effect of dietary selenium and tumor status on the retention of 75Se by tissues and mammary tumors of DMBA-treated rats. Biol. Trace Elem. Res. 20, 179–196 (1989).

    Article  PubMed  Google Scholar 

  47. Iwai, K., Maeda, H. & Konno, T. Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Res. 44, 2115–2121 (1984).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Heuser, L. S. & Miller, F. N. Differential macromolecular leakage from the vasculature of tumors. Cancer 57, 461–464 (1986).

    Article  CAS  PubMed  Google Scholar 

  50. Kreuter, J. Nanoparticle-based dmg delivery systems. J. Control. Release 16, 169–176 (1991).

    Article  CAS  Google Scholar 

  51. Oppenheim, R. C. Solid colloidal drug delivery systems: nanoparticles. Int. J. Pharm. 8, 217–234 (1981).

    Article  CAS  Google Scholar 

  52. Tabata, Y., Murakami, Y. & Ikada, Y. Photodynamic effect of polyethylene glycol-modified fullerene on tumor. Jpn. J. Cancer Res. 88, 1108–1116 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Allemann, E. et al. PEG‐coated poly(lactic acid) nanoparticles for the delivery of hexadecafluoro zinc phthalocyanine to EMT‐6 mouse mammary tumours. J. Pharm. Pharmacol. 47, 382–387 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Hodoshima, N. et al. Lipid nanoparticles for delivering antitumor drugs. Int. J. Pharm. 146, 81–92 (1997).

    Article  CAS  Google Scholar 

  55. Matsumura, Y., Oda, T. & Maeda, H. General mechanism of intratumor accumulation of macromolecules: advantage of macromolecular therapeutics. Gan Kagaku Ryoho Cancer Chemother. 14, 821–829 (1987).

    CAS  Google Scholar 

  56. Jain, R. K. Transport of molecules across tumor vasculature. Cancer Metastasis Rev. 6, 559–593 (1987).

    Article  CAS  PubMed  Google Scholar 

  57. Yuan, F. et al. Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. Cancer Res. 54, 3352–3356 (1994).

    CAS  PubMed  Google Scholar 

  58. Yuan, F. et al. Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res. 55, 3752–3756 (1995).

    CAS  PubMed  Google Scholar 

  59. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. 95, 4607–4612 (1998). This article presents electron microscopy images of nanoparticles entering the tumour via interendothelial gaps, suggesting a mechanism of enhanced permeability of the EPR effect.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhang, Y. et al. Strategies to improve tumor penetration of nanomedicines through nanoparticle design. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 11, e1519 (2019).

    Article  PubMed  Google Scholar 

  61. Bazak, R., Houri, M., Achy, S. E., Hussein, W. & Refaat, T. Passive targeting of nanoparticles to cancer: a comprehensive review of the literature. Mol. Clin. Oncol. 2, 904–908 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wang, M. & Thanou, M. Targeting nanoparticles to cancer. Pharmacol. Res. 62, 90–99 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Kalyane, D. et al. Employment of enhanced permeability and retention effect (EPR): Nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer. Mater. Sci. Eng. C 98, 1252–1276 (2019).

    Article  CAS  Google Scholar 

  64. Helmlinger, G., Netti, P. A., Lichtenbeld, H. C., Melder, R. J. & Jain, R. K. Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15, 778–783 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Leu, A. J., Berk, D. A., Lymboussaki, A., Alitalo, K. & Jain, R. K. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 60, 4324–4327 (2000).

    CAS  PubMed  Google Scholar 

  66. Padera, T. P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002). This article presents evidence that tumour lymphatics are dysfunctional and collapsed, suggesting a mechanism of poor lymphatic drainage of the EPR effect.

    Article  ADS  CAS  PubMed  Google Scholar 

  67. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Duncan, R. Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Pharm. Sci. Technol. Today 2, 441–449 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Duncan, R. The dawning era of polymer therapeutics. Nat. Rev. Drug Discov. 2, 347–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Ferrari, M. Cancer nanotechnology: opportunities and challenges. Nat. Rev. Cancer 5, 161–171 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Duncan, R. Polymer conjugates as anticancer nanomedicines. Nat. Rev. Cancer 6, 688–701 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Greish, K. Enhanced permeability and retention of macromolecular drugs in solid tumors: a royal gate for targeted anticancer nanomedicines. J. Drug Target. 15, 457–464 (2008).

    Article  Google Scholar 

  74. Maeda, H., Wu, J., Sawa, T., Matsumura, Y. & Hori, K. Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J. Control. Release 65, 271–284 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Grodzinski, P., Liu, C. H., Hartshorn, C. M., Morris, S. A. & Russell, L. M. NCI alliance for nanotechnology in cancer — from academic research to clinical interventions. Biomed. Microdevices 21, 32 (2019).

    Article  PubMed  Google Scholar 

  76. Ptak, K., Farrell, D., Panaro, N. J., Grodzinski, P. & Barker, A. D. The NCI alliance for nanotechnology in cancer: achievement and path forward. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2, 450–460 (2010).

    Article  PubMed  Google Scholar 

  77. Grodzinski, P. NCI cancer nanotechnology centers of excellence (CCNEs) — a full story to set the record straight. J. Control. Release 309, 341–342 (2019).

    Article  CAS  PubMed  Google Scholar 

  78. Prabhakar, U. et al. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 73, 2412–2417 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Fang, J., Islam, W. & Maeda, H. Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers. Adv. Drug Deliv. Rev. 157, 142–160 (2020).

    Article  CAS  PubMed  Google Scholar 

  80. Golombek, S. K. et al. Tumor targeting via EPR: strategies to enhance patient responses. Adv. Drug Deliv. Rev. 130, 17–38 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. Biancacci, I. et al. Monitoring EPR effect dynamics during nanotaxane treatment with theranostic polymeric micelles. Adv. Sci. 9, 2103745 (2022).

    Article  CAS  Google Scholar 

  83. MacMillan, P. et al. Toward predicting nanoparticle distribution in heterogeneous tumor tissues. Nano Lett. 23, 7197–7205 (2023).

    Article  ADS  CAS  PubMed  Google Scholar 

  84. Cheng, Y.-H., He, C., Riviere, J. E., Monteiro-Riviere, N. A. & Lin, Z. Meta-analysis of nanoparticle delivery to tumors using a physiologically based pharmacokinetic modeling and simulation approach. ACS Nano 14, 3075–3095 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Dai, Q. et al. Quantifying the ligand-coated nanoparticle delivery to cancer cells in solid tumors. ACS Nano 12, 8423–8435 (2018). This article established that only 0.0014% of injected nanoparticles are delivered to cancer cells.

    Article  CAS  PubMed  Google Scholar 

  86. Nguyen, L. N. M. et al. The exit of nanoparticles from solid tumours.Nat. Mater. 22, 1261–1272 (2023). This article reports that nanoparticles exit the tumour through the lymphatics in and around the tumour, and proposes the ATR principle as an alternative mechanism of nanoparticle delivery.

    Article  ADS  CAS  PubMed  Google Scholar 

  87. Petros, R. A. & DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 9, 615–627 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Sindhwani, S. et al. The entry of nanoparticles into solid tumours. Nat. Mater. 19, 566–575 (2020). This article reports that active transport processes of nanoparticle entry are dominant over passive transport.

    Article  ADS  CAS  PubMed  Google Scholar 

  89. Kingston, B. R. et al. Specific endothelial cells govern nanoparticle entry into solid tumors. ACS Nano 15, 14080–14094 (2021).

    Article  CAS  PubMed  Google Scholar 

  90. Thurston, G. et al. Cationic liposomes target angiogenic endothelial cells in tumors and chronic inflammation in mice. J. Clin. Invest. 101, 1401–1413 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Feng, D., Nagy, J. A., Dvorak, H. F. & Dvorak, A. M. Ultrastructural studies define soluble macromolecular, particulate, and cellular transendothelial cell pathways in venules, lymphatic vessels, and tumor‐associated microvessels in man and animals. Microsc. Res. Tech. 57, 289–326 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Desai, N. et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin. Cancer Res. 12, 1317–1324 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Kohn, S., Nagy, J. A., Dvorak, H. F. & Dvorak, A. M. Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab. Invest. 67, 596–607 (1992).

    CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  95. Harney, A. S. et al. Real-time imaging reveals local, transient vascular permeability, and tumor cell intravasation stimulated by TIE2hi macrophage-derived VEGFA. Cancer Discov. 5, 932–943 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Naumenko, V. A. et al. Extravasating neutrophils open vascular barrier and improve liposomes delivery to tumors. ACS Nano 13, 12599–12612 (2019).

    Article  CAS  PubMed  Google Scholar 

  97. Ballou, B. et al. Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjug. Chem. 18, 389–396 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Valdés-Olmos, R. A. et al. Evaluation of mammary lymphoscintigraphy by a single intratumoral injection for sentinel node identification. J. Nucl. Med. 41, 1500–1506 (2000).

    PubMed  Google Scholar 

  99. Liang, C. et al. Tumor metastasis inhibition by imaging‐guided photothermal therapy with single‐walled carbon nanotubes. Adv. Mater. 26, 5646–5652 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Liu, J. et al. Enhanced primary tumor penetration facilitates nanoparticle draining into lymph nodes after systemic injection for tumor metastasis inhibition. ACS Nano 13, 8648–8658 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Qin, L. et al. A tumor-to-lymph procedure navigated versatile gel system for combinatorial therapy against tumor recurrence and metastasis. Sci. Adv. 6, eabb3116 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  102. Jiang, X. et al. Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy. J. Immunother. Cancer 10, e003960 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Kwong, B., Gai, S. A., Elkhader, J., Wittrup, K. D. & Irvine, D. J. Localized immunotherapy via liposome-anchored anti-CD137 + IL-2 prevents lethal toxicity and elicits local and systemic antitumor immunity. Cancer Res. 73, 1547–1558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ludford, R. J. The vital staining of normal and malignant cells.-II. The staining of malignant tumours with trypan blue. Proc. R. Soc. Lond. B 104, 493–512 (1929).

    Article  ADS  Google Scholar 

  105. Lin, Z. P. et al. Macrophages actively transport nanoparticles in tumors after extravasation. ACS Nano 16, 6080–6092 (2022). This article reports that nanoparticle transport through the tumour occurs via cellular-based mechanisms, showing that perivascular macrophages sequester extravasated nanoparticles and transport them throughout the tumour.

    Article  CAS  PubMed  Google Scholar 

  106. 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  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  107. Haber, T. et al. Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles. Proc. Natl Acad. Sci. 117, 19737–19745 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Menard, J. A., Cerezo-Magaña, M. & Belting, M. Functional role of extracellular vesicles and lipoproteins in the tumour microenvironment. Philos. Trans. R. Soc. B Biol. Sci. 373, 20160480 (2018).

    Article  Google Scholar 

  110. Frankel, W. L. & Jin, M. Serosal surfaces, mucin pools, and deposits, Oh my: challenges in staging colorectal carcinoma. Mod. Pathol. 28, S95–S108 (2015).

    Article  PubMed  Google Scholar 

  111. Timpl, R. Structure and biological activity of basement membrane proteins. Eur. J. Biochem. 180, 487–502 (1989).

    Article  CAS  PubMed  Google Scholar 

  112. Yurchenco, P. D. Basement membranes: cell scaffoldings and signaling platforms. Cold Spring Harb. Perspect. Biol. 3, a004911 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kirkland, S. C. Type I collagen inhibits differentiation and promotes a stem cell-like phenotype in human colorectal carcinoma cells. Br. J. Cancer 101, 320–326 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Medici, D. & Nawshad, A. Type I collagen promotes epithelial–mesenchymal transition through ILK-dependent activation of NF-κB and LEF-1. Matrix Biol. 29, 161–165 (2010).

    Article  CAS  PubMed  Google Scholar 

  115. Januchowski, R. et al. Increased expression of several collagen genes is associated with drug resistance in ovarian cancer cell lines. J. Cancer 7, 1295–1310 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sherman-Baust, C. A. et al. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell 3, 377–386 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Yurchenco, P. D. & Ruben, G. C. Basement membrane structure in situ: evidence for lateral associations in the type IV collagen network. J. Cell Biol. 105, 2559–2568 (1987).

    Article  CAS  PubMed  Google Scholar 

  118. Pluen, A. et al. Role of tumor–host interactions in interstitial diffusion of macromolecules: cranial vs. subcutaneous tumors. Proc. Natl Acad. Sci. 98, 4628–4633 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lieleg, O., Baumgärtel, R. M. & Bausch, A. R. Selective filtering of particles by the extracellular matrix: an electrostatic bandpass. Biophys. J. 97, 1569–1577 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  121. Dancy, J. G. et al. Non-specific binding and steric hindrance thresholds for penetration of particulate drug carriers within tumor tissue. J. Control. Release 238, 139–148 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Sykes, E. A. et al. Tailoring nanoparticle designs to target cancer based on tumor pathophysiology. Proc. Natl Acad. Sci. 113, E1142–E1151 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wang, X. et al. Delivery of platinum(IV) drug to subcutaneous tumor and lung metastasis using bradykinin-potentiating peptide-decorated chitosan nanoparticles. Biomaterials 35, 6439–6453 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Appiah, E. et al. Acid-responsive HPMA copolymer-bradykinin conjugate enhances tumor-targeted delivery of nanomedicine. J. Control. Release 337, 546–556 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Gormley, A. J. et al. Guided delivery of polymer therapeutics using plasmonic photothermal therapy. Nano Today 7, 158–167 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zhen, Z. et al. Tumor vasculature targeted photodynamic therapy for enhanced delivery of nanoparticles. ACS Nano 8, 6004–6013 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sano, K., Nakajima, T., Choyke, P. L. & Kobayashi, H. Markedly enhanced permeability and retention effects induced by photo-immunotherapy of tumors. ACS Nano 7, 717–724 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Liang, C. et al. Nanoparticle-mediated internal radioisotope therapy to locally increase the tumor vasculature permeability for synergistically improved cancer therapies. Biomaterials 197, 368–379 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Ashton, J. R. et al. Dual-energy CT imaging of tumor liposome delivery after gold nanoparticle-augmented radiation therapy. Theranostics 8, 1782–1797 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Feng, D. et al. Pathways of macromolecular extravasation across microvascular endothelium in response to VPF/VEGF and other vasoactive mediators. Microcirculation 6, 23–44 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Dictor, M., Carlén, B., Bendsöe, N. & Flamholc, L. Ultrastructural development of Kaposi’s sarcoma in relation to the dermal microvasculature. Virchows Arch. 419, 35–43 (1991).

    Article  CAS  Google Scholar 

  132. Orenstein, J. M. Ultrastructure of Kaposi sarcoma. Ultrastruct. Pathol. 32, 211–220 (2008).

    Article  PubMed  Google Scholar 

  133. Jenny, B. et al. Expression and localization of VEGF‐C and VEGFR‐3 in glioblastomas and haemangioblastomas. J. Pathol. 209, 34–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Walkey, C. D. & Chan, W. C. W. Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem. Soc. Rev. 41, 2780–2799 (2011).

    Article  PubMed  Google Scholar 

  135. Cedervall, T. et al. Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles. Proc. Natl Acad. Sci. 104, 2050–2055 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  136. Tenzer, S. et al. Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. Nat. Nanotechnol. 8, 772–781 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  138. Yan, Y. et al. Differential roles of the protein corona in the cellular uptake of nanoporous polymer particles by monocyte and macrophage cell lines. ACS Nano 7, 10960–10970 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Ngo, W. et al. Identifying cell receptors for the nanoparticle protein corona using genome screens. Nat. Chem. Biol. 18, 1023–1031 (2022).

    Article  CAS  PubMed  Google Scholar 

  140. Goncalves, A. et al. Micellar lipid composition affects micelle interaction with class B scavenger receptor extracellular loops. J. Lipid Res. 56, 1123–1133 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hatami, E. et al. Mannose-decorated hybrid nanoparticles for enhanced macrophage targeting. Biochem. Biophys. Rep. 17, 197–207 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. Schnitzer, J. E. gp60 is an albumin-binding glycoprotein expressed by continuous endothelium involved in albumin transcytosis. Am. J. Physiol. Heart C. 262, H246–H254 (1992).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  144. Poon, W. et al. Elimination pathways of nanoparticles. ACS Nano 13, 5785–5798 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Tsoi, K. M. et al. Mechanism of hard-nanomaterial clearance by the liver. Nat. Mater. 15, 1212–1221 (2016).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  146. Choi, H. S. et al. Renal clearance of quantum dots. Nat. Biotechnol. 25, 1165–1170 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  148. Stylianopoulos, T., Munn, L. L. & Jain, R. K. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer 4, 292–319 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhang, Y.-N. et al. Nanoparticle size influences antigen retention and presentation in lymph node follicles for humoral immunity. Nano Lett. 19, 7226–7235 (2019).

    Article  ADS  CAS  PubMed  Google Scholar 

  150. Zhang, Y.-N., Poon, W., Sefton, E. & Chan, W. C. W. Suppressing subcapsular sinus macrophages enhances transport of nanovaccines to lymph node follicles for robust humoral immunity. ACS Nano 14, 9478–9490 (2020).

    Article  CAS  PubMed  Google Scholar 

  151. Nakamura, T. et al. The effect of size and charge of lipid nanoparticles prepared by microfluidic mixing on their lymph node transitivity and distribution. Mol. Pharm. 17, 944–953 (2020).

    Article  CAS  PubMed  Google Scholar 

  152. 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).

    Article  CAS  PubMed  Google Scholar 

  153. He, C., Hu, Y., Yin, L., Tang, C. & Yin, C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials 31, 3657–3666 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Liu, X. et al. Mixed‐charge nanoparticles for long circulation, low reticuloendothelial system clearance, and high tumor accumulation. Adv. Healthc. Mater. 3, 1439–1447 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  155. Wang, J. et al. Size- and surface chemistry-dependent pharmacokinetics and tumor accumulation of engineered gold nanoparticles after intravenous administration. Metallomics 7, 516–524 (2015).

    Article  CAS  PubMed  Google Scholar 

  156. Han, X. et al. Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation. J. Control. Release 197, 29–40 (2015).

    Article  CAS  PubMed  Google Scholar 

  157. Al-Jamal, W. T. et al. Tumor targeting of functionalized quantum dot−liposome hybrids by intravenous administration. Mol. Pharm. 6, 520–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  158. Goel, S. et al. VEGF121-conjugated mesoporous silica nanoparticle: a tumor targeted drug delivery system. ACS Appl. Mater. Inter. 6, 21677–21685 (2014).

    Article  CAS  Google Scholar 

  159. 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).

    Article  ADS  CAS  PubMed  Google Scholar 

  160. Arnida, Janát-Amsbury, M. M., Ray, A., Peterson, C. M. & Ghandehari, H. Geometry and surface characteristics of gold nanoparticles influence their biodistribution and uptake by macrophages.Eur. J. Pharm. Biopharm. 77, 417–423 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Mitchell, M. J. et al. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 20, 101–124 (2021).

    Article  CAS  PubMed  Google Scholar 

  162. 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  PubMed  PubMed Central  Google Scholar 

  163. Tylawsky, D. E. et al. P-selectin-targeted nanocarriers induce active crossing of the blood–brain barrier via caveolin-1-dependent transcytosis. Nat. Mater. 22, 391–399 (2023).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  164. Zhou, Q. et al. Enzyme-activatable polymer–drug conjugate augments tumour penetration and treatment efficacy. Nat. Nanotechnol. 14, 799–809 (2019).

    Article  CAS  PubMed  Google Scholar 

  165. Chen, S. et al. Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion–drug conjugates with cell-membrane affinity. Nat. Biomed. Eng. 5, 1019–1037 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Wang, Q. et al. Breaking through the basement membrane barrier to improve nanotherapeutic delivery to tumours.Nat. Nanotechnol. 19, 95–105 (2024).

    Article  ADS  CAS  PubMed  Google Scholar 

  167. Matsumoto, Y. et al. Vascular bursts enhance permeability of tumour blood vessels and improve nanoparticle delivery. Nat. Nanotechnol. 11, 533–538 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  168. Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts.Sci. Transl. Med. 9, eaal0225 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Foroozandeh, P. & Aziz, A. A. Insight into cellular uptake and intracellular trafficking of nanoparticles. Nanoscale Res. Lett. 13, 339 (2018).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  170. Wolfram, J. et al. A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery. Sci. Rep. 7, 13738 (2017).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

W.C.W.C. acknowledges Collaborative Health Research Program Grant CPG-146468, Canadian Institute of Health Research Grants FDN159932 and MOP-1301431, and Canadian Research Chairs Program Grant 950-223824. We thank NSERC (W.N. and S.M.M.), Ontario Graduate Scholarship (P.M. and S.M.M.), the Cecil Yip Award (W.N.), the Walter C. Sumner Foundation (P.M.), Vanier Canada Graduate Scholarship (S.M.M.), Jennifer Dorrington Award (S.M.M.) and the Wildcat Foundation (W.N.) for student fellowships and scholarships. We thank J. Rothschild and A. Zilman for commenting on the manuscript.

Author information

Authors and Affiliations

  1. Institute of Biomedical Engineering, University of Toronto, Rosebrugh Building, Toronto, Ontario, Canada

    Luan N. M. Nguyen, Wayne Ngo, Zachary P. Lin, Shrey Sindhwani, Stefan M. Mladjenovic & Warren C. W. Chan

  2. Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada

    Luan N. M. Nguyen, Wayne Ngo, Zachary P. Lin, Shrey Sindhwani, Presley MacMillan, Stefan M. Mladjenovic & Warren C. W. Chan

  3. Gladstone Institutes, San Francisco, CA, USA

    Wayne Ngo

  4. California Institute for Quantitative Biosciences, University of California Berkeley, Berkeley, CA, USA

    Wayne Ngo

  5. Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Shrey Sindhwani

  6. Department of Chemistry, University of Toronto, Toronto, Ontario, Canada

    Presley MacMillan & Warren C. W. Chan

  7. Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada

    Warren C. W. Chan

  8. Department of Material Science and Engineering, University of Toronto, Toronto, Ontario, Canada

    Warren C. W. Chan

Authors
  1. Luan N. M. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wayne Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zachary P. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shrey Sindhwani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Presley MacMillan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stefan M. Mladjenovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Warren C. W. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.N.M.N., S.S. and W.C.W.C. outlined the initial manuscript format. L.N.M.N., W.N. Z.P.L., S.S., P.M. and W.C.W.C. performed the literature search and wrote the initial manuscript draft. L.N.M.N., W.N., Z.P.L. and S.M.M. designed the figures. All authors participated in the writing and editing of the manuscript.

Corresponding author

Correspondence to Warren C. W. Chan.

Ethics declarations

Competing interests

The authors declare the following competing interests: W.C.W.C. is a co-founder of Luna Nanotech and consults for Foresite Capital, the Cystic Fibrosis Foundation, METiS Therapeutics, Moderna and Merck. L.N.M.N., W.N., Z.P.L., S.S., P.M. and S.M.M. declare no competing interests.

Peer review

Peer review information

Nature Reviews Bioengineering thanks Twan Lammers, Michael Mitchell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

Related links

The fundamental processes involved in or responsible for an action, reaction, or other natural phenomenon: https://www.merriam-webster.com/dictionary/mechanism

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nguyen, L.N.M., Ngo, W., Lin, Z.P. et al. The mechanisms of nanoparticle delivery to solid tumours. Nat Rev Bioeng 2, 201–213 (2024). https://doi.org/10.1038/s44222-024-00154-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44222-024-00154-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer