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Designing nanomedicine for immuno-oncology

Abstract

Two major obstacles facing cancer nanomedicine are the tendency of nanoparticles to be taken up by normal tissues and organs and the nanoparticles' inability to efficiently penetrate solid tumours. Although substantial efforts have been made to improve the intratumoural delivery of nanotherapeutics, many strategies have failed to produce meaningful clinical benefits. Recent advances in the field of immuno-oncology have led to drugs that boost the host's own immune system to fight cancer. In contrast to conventional therapies, which often target cancer cells, immunotherapies stimulate immune cells in ways that promote their recognition and the eradication of tumours. In this Perspective, we posit that this approach represents a new framework for cancer nanomedicine, and that immune-targeted nanomedicines could generate tumouricidal effects without the need to overcome the pathophysiological barriers that are intrinsic to the tumour microenvironment and that hinder nanoparticle delivery. The rational design of new immuno-oncology nanomedicines provides opportunities for developing the next generation of nanotherapeutics for cancer patients.

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Figure 1: Systemically delivered nanoparticles are cleared from the bloodstream and accumulate in several tissues or organs before entering the tumour.
Figure 2: Active and passive delivery of nanoparticles into tumours.
Figure 3: Tumour- and stromal-targeted cancer nanomedicine.
Figure 4: Strategies for nanomedicine to target different steps along the immune cascade in cell-mediated immunity.
Figure 5: A cancer-nanomedicine model for immuno-oncology.
Figure 6: Nanomedicine strategies for enhancing antitumour immune responses.

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References

  1. Allen, T. M. & Cullis, P. R. Drug delivery systems: entering the mainstream. Science 303, 1818–1822 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Hurria, A. et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J. Clin. Oncol. 29, 3457–3465 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sawyer, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

    Article  CAS  Google Scholar 

  4. Haber, D. A., Gray, N. S. & Baselga, J. The evolving war on cancer. Cell 145, 19–24 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. O'Brien, S. G. et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348, 994–1004 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9, 550–562 (2009).

    Article  CAS  PubMed  Google Scholar 

  7. Peer, D. et al. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotech. 2, 751–760 (2007).

    Article  CAS  Google Scholar 

  8. Chow, E. K. & Ho, D. Cancer nanomedicine: from drug delivery to imaging. Sci. Transl. Med. 5, 216rv4 (2013).

    Article  PubMed  CAS  Google Scholar 

  9. Harris, J. M. & Chess, R. B. Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2, 214–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Roderiguez, P. L. et al. Minimal “self” peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles. Science 339, 971–975 (2013).

    Article  CAS  Google Scholar 

  11. Parodi, A. et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membrane possess cell-like functions. Nat. Nanotech. 8, 61–68 (2013).

    Article  CAS  Google Scholar 

  12. Hu, C. J. et al. Nanoparticle biointerfacing by platelet membrane cloaking. Nature 526, 118–121 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cho, K., Wang, X., Nie, S., Chen, Z. & Shin, D. M. Therapeutic nanoparticles for drug delivery in cancer. Clin. Cancer Res. 4, 1310–1316 (2008).

    Article  CAS  Google Scholar 

  14. Farokhzad, O. C. et al. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl Acad. Sci. USA 103, 6315–6320 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang, A. Z., Langer, R. & Farokhzad, O. C. Nanoparticle delivery of cancer drugs. Annu. Rev. Med. 63, 185–198 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Trédan, O., Galmarini, C. M., Patel, K. & Tannock, I. F. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99, 1441–1454 (2007).

    Article  PubMed  CAS  Google Scholar 

  17. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Hashizume, H. et al. Openings between defective endothelial cells explain tumor vessel leakiness. Am. J. Pathol. 156, 1363–1380 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. 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 

  22. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 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  CAS  PubMed  Google Scholar 

  25. Jiang, W., Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Advances and challenges of nanotechnology-based drug delivery systems. Expert Opin. Drug Deliv. 4, 621–633 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. von Roemeling, C. A., Jiang, W., Chan, C. K., Weissman, I. L. & Kim, B. Y. S. Breaking down the barriers to precision cancer nanomedicine. Trends Biotechnol. 35, 159–171 (2017).

    Article  CAS  PubMed  Google Scholar 

  27. Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2010).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Xiao, K. et al. The effect of surface charge on in vivo distribution of PEG-oligocholic acid based micellar nanoparticles. Biomaterials 32, 3435–3446 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  33. 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. USA 104, 2050–2055 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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 

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

    Article  CAS  PubMed  Google Scholar 

  36. Nel, A. E. et al. Understanding biophysicochemical interactions at the nano–bio interface. Nat. Mater. 8 543–557 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Qie, Y. et al. Surface modification of nanoparticles enables selective evasion of phagocytic clearance by distinct macrophage phenotypes. Sci. Rep. 6, 26269 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hamilton, A. et al. EORTC 10968: a phase I clinical and pharmacokinetic study of polyethylene glycol liposomal doxorubicin (Caelyx, Doxil) at a 6-week interval in patients with metastatic breast cancer. European Organisation for Research and Treatment of Cancer. Ann. Oncol. 13, 910–918 (2002).

    Article  CAS  PubMed  Google Scholar 

  40. Schottler, S. et al. Protein adsorption is required for stealth effect of poly(ethyleneglycol)- and poly(phosphoester)-coated nanocarriers. Nat. Nanotech. 11, 372–377 (2016).

    Article  CAS  Google Scholar 

  41. Hu, C. M. et al. Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform. Proc. Natl Acad. Sci. USA 108, 10980–10985 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guo, Y. et al. Erythrocyte membrane-enveloped polymeric nanoparticles as nanovaccine for induction of antitumor immunity against melanoma. ACS Nano 9, 6918–6933 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Molinaro, R. et al. Biomimetic proteolipid vesicles for targeting inflamed tissues. Nat. Mater. 15, 1037–1046 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Felfoul, O. et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nat. Nanotech. 11 941–947 (2016).

    Article  CAS  Google Scholar 

  45. Takizawa, H. & Manz, M. G. Macrophage tolerance: CD47–SIRP-α-mediated signals matter. Nat. Immunol. 8, 1287–1289 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Kurts, C., Panzer, U., Anders, H. J. & Rees, A. J. The immune system and kidney disease: basic concepts and clinical implications. Nat. Rev. Immunol. 13, 738–753 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Deen, W. M., Lazzara, M. J. & Meyers, B. D. Structural determinants of glomerular permeability. Am. J. Physiol. Renal Physiol. 281, F579–F596 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Liu, J. Y. et al. Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology. Mater. Today 16, 477–486 (December, 2013).

    Article  CAS  Google Scholar 

  50. Schrier, R. W. Cancer therapy and renal injury. J. Clin. Invest. 110, 743–745 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Groothuis, D. R. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro. Oncol. 2, 45–59 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Su, L., Mruk, D. D. & Cheng, C. Y. Drug transporters, the blood-testis barrier, and spermatogenesis. J. Endocrinol. 208, 207–223 (2011).

    CAS  PubMed  Google Scholar 

  53. Koffie, R. M. et al. Nanoparticles enhance brain delivery of blood-brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging. Proc. Natl Acad. Sci. USA 108, 18837–18842 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zensi, A. et al. Human serum albumin nanoparticles modified with apolipoprotein A-I cross the blood-brain barrier and enter the rodent brain. J. Drug Target. 18, 842–848 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Schroeder, A. et al. Treating metastatic cancer with nanotechnology. Nat. Rev. Cancer 12, 39–50 (2012).

    Article  CAS  Google Scholar 

  56. Carpentier, A. et al. Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci. Transl. Med. 8, 343re2 (2016).

    Article  PubMed  CAS  Google Scholar 

  57. Maeda, H., Nakamura, H. & Fang, J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv. Drug Deliv. Rev. 65, 71–79 (2013).

    Article  CAS  PubMed  Google Scholar 

  58. Hobbs, S. K. et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95, 4607–4612 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Padera, T. P. et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Adiseshaiah, P. P., Crist, R. M., Hook, S. S. & McNeil, S. E. Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer. Nat. Rev. Clin. Oncol. 13, 750–765 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Balkwill, F. R., Capasso, M. & Hagemann, T. The tumor microenvironment at a glance. J. Cell Sci. 125, 5591–5596 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Allen, T. M. Ligand-targeted therapeutics in anticancer therapy. Nat. Rev. Cancer 2, 750–763 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Kim, B. Y. S. et al. Biodegradable quantum dot nanocomposites enable live cell labeling and imaging of cytoplasmic targets. Nano Lett. 8, 3887–3892 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Gao, X., Cui, Y., Levenson, R. M., Chung, L. W. K. & Nie, S. In vivo cancer targeting and imaging with semiconductor quantum dots. Nat. Biotechnol. 22, 969–976 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Choi, H. S. et al. Design considerations for tumour-targeted nanoparticles. Nat. Nanotech. 5 42–47 (2010).

    Article  CAS  Google Scholar 

  67. Peng, L. et al. Combinatorial chemistry identifies high-affinity peptidomimetics against α4β1 integrin for in vivo tumor imaging. Nat. Chem. Biol. 2, 381–389 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Jiang, W., Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Nanoparticle-mediated cellular response is size-dependent. Nat. Nanotech. 3, 145–150 (2008).

    Article  CAS  Google Scholar 

  69. Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer. Nat. Rev. Cancer 12, 278–287 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Chan, A. C. & Carter, P. J. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 10, 301–316 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Van Cutsem, E. et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Hudis, C. A. Trastuzumab-mechanism of action and use in clinical practice. N. Engl. J. Med. 357, 39–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Cheson, B. D. & Leonard, J. P. Monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N. Engl. J. Med. 359, 613–626 (2008).

    Article  CAS  PubMed  Google Scholar 

  74. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Tolcher, A. W. et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–484 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  77. Joyce, J. A. Therapeutic targeting of the tumor microenvironment. Cancer Cell 7, 513–520 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Arap, W., Pasqualini, R. & Ruoslahti, E. Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science 279, 377–380 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Sugahara, K. N. et al. Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell 16, 510–520 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ruoslahti, E., Bhatia, S. N. & Sailor, M. J. Targeting of drugs and nanoparticles to tumors. J. Cell. Biol. 188, 759–768 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81 Teesalu, T., Sugahara, K. N., Kotamraju, V. R. & Ruoslahti, E. C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl Acad. Sci. USA 106, 16157–16162 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Simberg, D. et al. Biomimetic amplification of nanoparticle homing to tumors. Proc. Natl Acad. Sci. USA 104, 932–936 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Messerschmidt, S. K. et al. Targeted lipid-coated nanoparticles: delivery of tumor necrosis factor-functionalized particles to tumor cells. J. Control. Release 137, 69–77 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Weissleder, R., Nahrendorf, M. & Pittet, M. J. Imaging macrophages with nanoparticles. Nat. Mater. 13, 125–138 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Zhang, B. et al. Targeting fibronectins of glioma extracellular matrix by CLT1 peptide-conjugated nanoparticles. Biomaterials 35, 4088–4098 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug. Discov. 10, 417–427 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  88. Jiang, W., Huang, Y. H., An, Y. & Kim, B. Y. S. Remodeling tumor vasculature to enhance delivery of intermediate-sized nanoparticles. ACS Nano 9, 8689–8696 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Cabral, H. et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat. Nanotech. 6, 815–823 (2011).

    Article  CAS  Google Scholar 

  90. Pardoll, D. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    Article  PubMed  Google Scholar 

  92. Motzer, R. J. et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N. Engl. J. Med. 373, 1803–1813 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Nghiem, P. T. et al. PD-1 blockade with pembrolizumab in advanced Merkel cell carcinoma. N. Engl. J. Med. 374, 2542–2552 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yang, Y. Cancer immunotherapy: harnessing the immune system to battle cancer. J. Clin. Invest. 125, 3335–3337 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Palucka, K. & Banchereau, J. Cancer immunotherapy via dendritic cells. Nat. Rev. Cancer 12, 265–277 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ravichandran, K. S. Beginnings of a good apoptotic meal: the find-me and eat-me signaling pathways. Immunity 35, 445–455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chao, M. P. et al. Calreticulin is the dominant pro-phagocytic signal on multiple human cancers and is counterbalanced by CD47. Sci. Transl. Med. 2, 63ra94 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Morvan, M. G. & Lanier, L. L. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271–285 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Willingham, S. B. et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl Acad. Sci. USA 109, 6662–6667 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Tsai, R. K. & Discher, D. E. Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells. J. Cell Biol. 180, 989–1003 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Anderson, A. C. Tim-3, a negative regulator of anti-tumor immunity. Curr. Opin . Immunol. 24, 213–216 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Bubeník, J. MHC class I down-regulation: tumour escape from immune surveillance?. Int. J. Oncol. 25, 487–491 (2004).

    PubMed  Google Scholar 

  107. Marvel, D. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J. Clin. Invest. 125, 3356–3364 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Holmgaard, R. B. et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 13, 412–424 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

    Article  CAS  PubMed  Google Scholar 

  111. Kerkar, S. P. & Restifo, N. P. Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 72, 3125–3130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defense for cancer immunotherapy. Nature 534, 396–401 (2016).

    Article  PubMed  CAS  Google Scholar 

  113. Sager, H. B. et al. RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci. Transl. Med. 8, 342ra80> (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  115. Hawkin, M. J., Soon-Shiong, P. & Desai, N. Protein nanoparticles as drug carriers in clinical medicine. Adv. Drug Deliv. Rev. 60, 876–885 (2008).

    Article  CAS  Google Scholar 

  116. Postow, M. A. et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372, 2006–2017 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    Article  PubMed  CAS  Google Scholar 

  119. Li, A. V. et al. Generation of effector memory T cell-based mucosal and systemic immunity with pulmonary nanoparticle vaccination. Sci. Transl. Med. 5, 204ra130 (2013).

    PubMed  PubMed Central  Google Scholar 

  120. Cho, N. H. et al. A multifunctional core–shell nanoparticle for dendritic cell-based cancer immunotherapy. Nat. Nanotech. 6, 675–682 (2011).

    Article  CAS  Google Scholar 

  121. Moon, J. J. et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat. Mater. 10, 243–251 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lizotte, P. H. et al. In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nat. Nanotech. 11 295–303 (2016).

    Article  CAS  Google Scholar 

  123. Li, H., Li, Y., Jiao, J. & Hu, H. M. Alpha-alumina nanoparticles induce efficient autophagy-dependent cross-presentation and potent antitumour response. Nat. Nanotech. 6, 645–650 (2011).

    Article  CAS  Google Scholar 

  124. Albert, L. J. & Inman, R. D. Molecular mimicry and autoimmunity. N. Engl. J. Med. 341, 2068–2074 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Leuschner, F. et al. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat. Biotechnol. 29, 1005–1010 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yin, H. et al. Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo. Nat. Biotechnol. 34, 328–333 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sunshine, J. C. & Green, J. J. Nanoengineering approaches to the design of artificial antigen-presenting cells. Nanomedicine 8, 1173–1189 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Andre, F., Escudier, B., Angevin, E., Tursz, T. & Zitvogel, L. Exosomes for cancer immunotherapy. Ann. Oncol. 15, iv141–iv144 (2004).

    Article  PubMed  Google Scholar 

  129. Théry, C., Ostrowski, M. & Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9, 581–593 (2009).

    Article  PubMed  CAS  Google Scholar 

  130. Utsugi-Kobukai, S., Fujimaki, H., Hotta, C., Nakazawa, M. & Minami, M. MHC class I-mediated exogenous antigen presentation by exosomes secreted from immature and mature bone marrow derived dendritic cells. Immunol. Lett. 89, 125–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Pitt, J. M. et al. Dendritic cell-derived exosomes as immunotherapies in the fight against cancer. J. Immunol. 193, 1006–1011 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Besse, B. et al. Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC. Oncoimmunology 5, e1071008 (2016).

    Article  PubMed  CAS  Google Scholar 

  133. 133 Chen, Q. et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun. 7, 13193 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kullberg, M., Martinson, H., Mann, K. & Anchordoquy, T. J. Complement C3 mediated targeting of liposomes to granulocytic myeloid derived suppressor cells. Nanomedicine 11, 1355–1363 (2015).

    Article  CAS  PubMed  Google Scholar 

  135. Novobrantseva, T. I. et al. Systemic RNAi-mediated gene silencing in nonhuman primate and rodent myeloid cells. Molecular Therapy Nucleic Acids 1, e4 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotech. 11, 986–994 (2016).

    Article  CAS  Google Scholar 

  137. Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen, P. L. et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 6, 1–11 (2016).

    Article  Google Scholar 

  141. Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Gainor, J. F. Moving programmed death-1 inhibitors to the front lines in non-small-cell lung cancer. J. Clin. Oncol. 34, 2953–2955 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. St John, A. L. et al. Synthetic mast-cell granules as adjuvants to promote and polarize immunity in lymph nodes. Nat. Mater. 11, 250–257 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Goldberg, M. S. Immunoengineering: how nanotechnology can enhance cancer immunotherapy. Cell 161, 201–204 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Sato, K. et al. Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy. Sci. Transl. Med. 8, 352ra110 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  147. Weissig, V., Pettinger, T. K. & Murdock, N. Nanopharmaceuticals (part 1): products on the market. Int. J. Nanomedicine 9, 4357–4373 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bozzuto, G. & Molinari, A. Liposomes as nanomedical devices. Int. J. Nanomedicine 10, 975–999 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Arvedson, T., O'Kelly, J. & Yang, B. B. Design rationale and development approach for pegfilgrastim as a long-acting granulocyte colony-stimulating factor. BioDrugs 29, 185–198 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  151. Aaron, C. & Anselmo, S. M. Nanoparticles in the clinic. Bioeng. Transl. Med. 1, 10–29 (2016).

    Article  Google Scholar 

  152. Park, J. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 1, 1 895–905 (2012).

    Article  CAS  Google Scholar 

  153. Eck, W. et al. Anti-CD4-targeted gold nanoparticles induce specific contrast enhancement of peripheral lymph nodes in X-ray computed tomography of live mice. Nano Lett. 10, 2318–2322 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by The Jorge and Leslie Bacardi Fund for the study of Regenerative Medicine (to B.Y.S.K.), the Mayo Clinic Center for Regenerative Medicine (to B.Y.S.K.), the James C. and Sara K. Kennedy Award (to B.Y.S.K.), the Mayo Clinic Center for Individualized Medicine Gerstner Family Award (to B.Y.S.K.), the JLG Brain Cancer Foundation and Richard D. and Darlene R. DeMars Award (to B.Y.S.K.), the Strawn Family Development Award (to B.Y.S.K.), the Helene Houle Career Development Award in Neurologic Surgery Research (to B.Y.S.K.) and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center). The authors thank C. Wogan of the MD Anderson Cancer Center's Division of Radiation Oncology for editorial assistance.

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W.J., J.C. and B.Y.S.K. conceived the work. W.J., C.A.V. and Y.C. carried out the literature search. W.J. and Y.Q. designed and generated the figures. All authors contributed to writing the manuscript.

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Correspondence to Wen Jiang or Betty Y. S. Kim.

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Jiang, W., von Roemeling, C., Chen, Y. et al. Designing nanomedicine for immuno-oncology. Nat Biomed Eng 1, 0029 (2017). https://doi.org/10.1038/s41551-017-0029

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