Plant Virus-Based Nanotechnologies

  • Amy M. Wen
  • Karin L. Lee
  • Nicole F. SteinmetzEmail author
Part of the Women in Engineering and Science book series (WES)


Nanoscale engineering is revolutionizing disease detection and prevention. Viruses have made a remarkable contribution to these developments because they can function as prefabricated nanoparticles that have naturally evolved to deliver cargos to cells and tissues. The Steinmetz Lab has established a library of plant virus-based nanoparticles and carried out comprehensive structure–function studies that have shown how to tailor these nanomaterials appropriately for biomedical applications. By exploiting the benefits of synthetic and chemical biology, plant virus-based nanotechnologies are being developed for applications in molecular imaging and drug delivery, and as cancer vaccines and immunotherapies.


Plant virus nanotechnology Viral nanoparticles (VNPs) Virus-like particles (VLPs) Molecular imaging Drug delivery Immunotherapy Vaccines 



This was funded in part by the following grants to N.F.S.: NIH R01-CA224605, NIH R01-HL137674, NIH U01-CA218292, NIH R21-EB024874, NIH R01-CA202814, NIH R21-HL121130, NIH R21-EB020946, American Cancer Society 128319-RSG-15-144-01-CDD, NSF DMR-1452257 CAREER, NSF CMMI-1333651, NSF CHE-1306447, and Susan G. Komen CCR14298962. A.M.W. was supported through the following fellowships: NIH T32 EB007509, AHA 15PRE25710044, and NIH F31 HL129703, and K.L.L. was supported by the following fellowships: NIH T32 EB007509 and NIH R25 CA148052.


  1. Adis International Ltd. (2003). HIV Gp120 vaccine - VaxGen: AIDSVAX, AIDSVAX B/B, AIDSVAX B/E, HIV Gp120 Vaccine - Genentech, HIV Gp120 Vaccine AIDSVAX - VaxGen, HIV Vaccine AIDSVAX – VaxGen. Drugs in R&D, 4(4), 249–253.CrossRefGoogle Scholar
  2. Aljabali, A. A. A., Lomonossoff, G. P., & Evans, D. J. (2011). CPMV-polyelectrolyte-templated gold nanoparticles. Biomacromolecules, 12(7), 2723–2728.CrossRefGoogle Scholar
  3. Bruckman, M. A., Kaur, G., Lee, L. A., Xie, F., Sepulveda, J., Breitenkamp, R., Zhang, X., Joralemon, M., Russell, T. P., Emrick, T., & Wang, Q. (2008). Surface modification of tobacco mosaic virus with “click” chemistry. Chembiochem: A European Journal of Chemical Biology, 9(4), 519–523.CrossRefGoogle Scholar
  4. Bruckman, M. A., Jiang, K., Simpson, E. J., Randolph, L. N., Luyt, L. G., Yu, X., & Steinmetz, N. F. (2014a). Dual-modal magnetic resonance and fluorescence imaging of atherosclerotic plaques in vivo using VCAM-1 targeted tobacco mosaic virus. Nano Letters, 14(3), 1551–1558.CrossRefGoogle Scholar
  5. Bruckman, M. A., Randolph, L. N., VanMeter, A., Hern, S., Shoffstall, A. J., Taurog, R. E., & Steinmetz, N. F. (2014b). Biodistribution, pharmacokinetics, and blood compatibility of native and PEGylated tobacco mosaic virus nano-rods and -spheres in mice. Virology, 449, 163–173.CrossRefGoogle Scholar
  6. Bruckman, M. A., VanMeter, A., & Steinmetz, N. F. (2015). Nanomanufacturing of tobacco mosaic virus-based spherical biomaterials using a continuous flow method. ACS Biomaterials Science & Engineering, 1(1), 13–18.CrossRefGoogle Scholar
  7. Cao, J., Guenther, R. H., Sit, T. L., Lommel, S. A., Opperman, C. H., & Willoughby, J. A. (2015). Development of abamectin loaded plant virus nanoparticles for efficacious plant parasitic nematode control. ACS Applied Materials & Interfaces, 7(18), 9546–9553.CrossRefGoogle Scholar
  8. Chackerian, B., Rangel, M., Hunter, Z., & Peabody, D. S. (2006). Virus and virus-like particle-based immunogens for Alzheimer’s disease induce antibody responses against amyloid-beta without concomitant T cell responses. Vaccine, 24(37–39), 6321–6331.CrossRefGoogle Scholar
  9. Chariou, P. L., & Steinmetz, N. F. (2017). Delivery of pesticides to plant parasitic nematodes using tobacco mild green mosaic virus as a nanocarrier. ACS Nano, 11(5), 4719–4730.CrossRefGoogle Scholar
  10. Czapar, A. E., Zheng, Y.-R., Riddell, I. A., Shukla, S., Awuah, S. G., Lippard, S. J., & Steinmetz, N. F. (2016). Tobacco mosaic virus delivery of phenanthriplatin for cancer therapy. ACS Nano, 10(4), 4119–4126.CrossRefGoogle Scholar
  11. Douglas, T., Strable, E., Willits, D., Aitouchen, A., Libera, M., & Young, M. (2002). Protein engineering of a viral cage for constrained nanomaterials synthesis. Advanced Materials, 14(6), 415–418.CrossRefGoogle Scholar
  12. Eber, F. J., Eiben, S., Jeske, H., & Wege, C. (2014). RNA-controlled assembly of tobacco mosaic virus-derived complex structures: From nanoboomerangs to tetrapods. Nanoscale, 7(1), 344–355.CrossRefGoogle Scholar
  13. Farkas, M. E., Aanei, I. L., Behrens, C. R., Tong, G. J., Murphy, S. T., O’Neil, J. P., & Francis, M. B. (2013). PET imaging and biodistribution of chemically modified bacteriophage MS2. Molecular Pharmaceutics, 10(1), 69–76.CrossRefGoogle Scholar
  14. Fulurija, A., Lutz, T. A., Sladko, K., Osto, M., Wielinga, P. Y., Bachmann, M. F., & Saudan, P. (2008). Vaccination against GIP for the treatment of obesity. PloS One, 3(9), e3163.CrossRefGoogle Scholar
  15. Geiger, F. C., Eber, F. J., Eiben, S., Mueller, A., Jeske, H., Spatz, J. P., & Wege, C. (2013). TMV nanorods with programmed longitudinal domains of differently addressable coat proteins. Nanoscale, 5(9), 3808–3816.CrossRefGoogle Scholar
  16. Gerlich, W. H. (2015). Prophylactic vaccination against hepatitis B: Achievements, challenges and perspectives. Medical Microbiology and Immunology, 204(1), 39–55.CrossRefGoogle Scholar
  17. Harper, D. M. (2009). Currently approved prophylactic HPV vaccines. Expert Review of Vaccines, 8(12), 1663–1679.CrossRefGoogle Scholar
  18. Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., & Bauer, S. (2004). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science (New York, N.Y.), 303(5663), 1526–1529.CrossRefGoogle Scholar
  19. Henao-Restrepo, A. M., Camacho, A., Longini, I. M., Watson, C. H., Edmunds, W. J., Egger, M., Carroll, M. W., Dean, N. E., Diatta, I., Doumbia, M., Draguez, B., Duraffour, S., Enwere, G., Grais, R., Gunther, S., Gsell, P.-S., Hossmann, S., Watle, S. V., Kondé, M. K., Kéïta, S., Kone, S., Kuisma, E., Levine, M. M., Mandal, S., Mauget, T., Norheim, G., Riveros, X., Soumah, A., Trelle, S., Vicari, A. S., Røttingen, J.-A., & Kieny, M.-P. (2017). Efficacy and effectiveness of an RVSV-vectored vaccine in preventing Ebola virus disease: Final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). The Lancet, 389(10068), 505–518.CrossRefGoogle Scholar
  20. Hortobagyi, G. N. (2005). Trastuzumab in the treatment of breast cancer. New England Journal of Medicine, 353(16), 1734–1736.CrossRefGoogle Scholar
  21. Hou, B., Saudan, P., Ott, G., Wheeler, M. L., Ji, M., Kuzmich, L., Lee, L. M., Coffman, R. L., Bachmann, M. F., & DeFranco, A. L. (2011). Selective utilization of toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity, 34(3), 375–384.CrossRefGoogle Scholar
  22. Hovlid, M. L., Lau, J. L., Breitenkamp, K., Higginson, C. J., Laufer, B., Manchester, M., & Finn, M. G. (2014). Encapsidated atom-transfer radical polymerization in Qβ virus-like nanoparticles. ACS Nano, 8(8), 8003–8014.CrossRefGoogle Scholar
  23. Huang, X., Bronstein, L. M., Retrum, J., Dufort, C., Tsvetkova, I., Aniagyei, S., Stein, B., Stucky, G., McKenna, B., Remmes, N., Baxter, D., Kao, C. C., & Dragnea, B. (2007). Self-assembled virus-like particles with magnetic cores. Nano Letters, 7(8), 2407–2416.CrossRefGoogle Scholar
  24. Jegerlehner, A., Maurer, P., Bessa, J., Hinton, H. J., Kopf, M., & Bachmann, M. F. (2007). TLR9 signaling in B cells determines class switch recombination to IgG2a. Journal of Immunology (Baltimore, MD: 1950), 178(4), 2415–2420.CrossRefGoogle Scholar
  25. Jhaveri, K., & Esteva, F. J. (2014). Pertuzumab in the treatment of HER2+ breast cancer. Journal of the National Comprehensive Cancer Network: JNCCN, 12(4), 591–598.CrossRefGoogle Scholar
  26. Klem, M. T., Willits, D., Young, M., & Douglas, T. (2003). 2-D array formation of genetically engineered viral cages on Au surfaces and imaging by atomic force microscopy. Journal of the American Chemical Society, 125(36), 10806–10807.CrossRefGoogle Scholar
  27. Knez, M., Bittner, A. M., Boes, F., Wege, C., Jeske, H., Maiβ, E., & Kern, K. (2003). Biotemplate synthesis of 3-Nm nickel and cobalt nanowires. Nano Letters, 3(8), 1079–1082.CrossRefGoogle Scholar
  28. Knobler, S., Lederberg, J., Pray, L. A., & Institute of Medicine (U.S.) (Eds.). (2002). Considerations for viral disease eradication: Lessons learned and future strategies: Workshop summary. Washington, DC: National Academy Press.Google Scholar
  29. Kohlhapp, F. J., Zloza, A., & Kaufman, H. L. (2015). Talimogene laherparepvec (T-VEC) as cancer immunotherapy. Drugs of Today (Barcelona, Spain: 1998), 51(9), 549–558.Google Scholar
  30. Koonin, E. V., Senkevich, T. G., & Dolja, V. V. (2006). The ancient virus world and evolution of cells. Biology Direct, 1, 29.CrossRefGoogle Scholar
  31. Le, D. H. T., Lee, K. L., Shukla, S., Commandeur, U., & Steinmetz, N. F. (2017). Potato virus X, a filamentous plant viral nanoparticle for doxorubicin delivery in cancer therapy. Nanoscale, 9(6), 2348–2357.CrossRefGoogle Scholar
  32. Lebel, M.-È., Chartrand, K., Tarrab, E., Savard, P., Leclerc, D., & Lamarre, A. (2016). Potentiating cancer immunotherapy using papaya mosaic virus-derived nanoparticles. Nano Letters, 16(3), 1826–1832.CrossRefGoogle Scholar
  33. Lee, K. L., Carpenter, B. L., Wen, A. M., Ghiladi, R. A., & Steinmetz, N. F. (2016). High aspect ratio nanotubes formed by tobacco mosaic virus for delivery of photodynamic agents targeting melanoma. ACS Biomaterials Science & Engineering, 2(5), 838–844.CrossRefGoogle Scholar
  34. Lee, K. L., Murray, A. A., Le, D. H. T., Sheen, M. R., Shukla, S., Commandeur, U., Fiering, S., & Steinmetz, N. F. (2017). Combination of plant virus nanoparticle-based in situ vaccination with chemotherapy potentiates antitumor response. Nano Letters, 17(7), 4019–4028.CrossRefGoogle Scholar
  35. Lizotte, P. H., Wen, A. M., Sheen, M. R., Fields, J., Rojanasopondist, P., Steinmetz, N. F., & Fiering, S. (2015). In situ vaccination with cowpea mosaic virus nanoparticles suppresses metastatic cancer. Nature Nanotechnology, 11(3), 295–303.CrossRefGoogle Scholar
  36. Loo, L., Guenther, R. H., Lommel, S. A., & Franzen, S. (2007). Encapsidation of nanoparticles by red clover necrotic mosaic virus. Journal of the American Chemical Society, 129(36), 11111–11117.CrossRefGoogle Scholar
  37. López-Macías, C., Ferat-Osorio, E., Tenorio-Calvo, A., Isibasi, A., Talavera, J., Arteaga-Ruiz, O., Arriaga-Pizano, L., Hickman, S. P., Allende, M., Lenhard, K., Pincus, S., Connolly, K., Raghunandan, R., Smith, G., & Glenn, G. (2011). Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine in a blinded, randomized, placebo-controlled trial of adults in Mexico. Vaccine, 29(44), 7826–7834.CrossRefGoogle Scholar
  38. Lua, L. H. L., Connors, N. K., Sainsbury, F., Chuan, Y. P., Wibowo, N., & Middelberg, A. P. J. (2014). Bioengineering virus-like particles as vaccines: Virus-like particles as vaccines. Biotechnology and Bioengineering, 111(3), 425–440.CrossRefGoogle Scholar
  39. Luque, D., de la Escosura, A., Snijder, J., Brasch, M., Burnley, R. J., Koay, M. S. T., Carrascosa, J. L., Wuite, G. J. L., Roos, W. H., Heck, A. J. R., Cornelissen, J. J. L. M., Torres, T., & Castón, J. R. (2013). Self-assembly and characterization of small and monodisperse dye nanospheres in a protein cage. Chemical Science, 5(2), 575–581.CrossRefGoogle Scholar
  40. Miller, R. A., Presley, A. D., & Francis, M. B. (2007). Self-assembling light-harvesting systems from synthetically modified tobacco mosaic virus coat proteins. Journal of the American Chemical Society, 129(11), 3104–3109.CrossRefGoogle Scholar
  41. Pokorski, J. K., & Steinmetz, N. F. (2011). The art of engineering viral nanoparticles. Molecular Pharmaceutics, 8(1), 29–43.CrossRefGoogle Scholar
  42. Prangishvili, D., & Garrett, R. A. (2005). Viruses of hyperthermophilic crenarchaea. Trends in Microbiology, 13(11), 535–542.CrossRefGoogle Scholar
  43. Prangishvili, D., Forterre, P., & Garrett, R. A. (2006). Viruses of the Archaea: A unifying view. Nature Reviews Microbiology, 4(11), 837–848.CrossRefGoogle Scholar
  44. Quentin, M., Abad, P., & Favery, B. (2013). Plant parasitic nematode effectors target host defense and nuclear functions to establish feeding cells. Frontiers in Plant Science, 4, 53.CrossRefGoogle Scholar
  45. Rachel, R., Bettstetter, M., Hedlund, B. P., Häring, M., Kessler, A., Stetter, K. O., & Prangishvili, D. (2002). Remarkable morphological diversity of viruses and virus-like particles in hot terrestrial environments. Archives of Virology, 147(12), 2419–2429.CrossRefGoogle Scholar
  46. Riedel, S. (2005). Edward Jenner and the history of smallpox and vaccination. Proceedings (Baylor University Medical Center), 18(1), 21–25.CrossRefGoogle Scholar
  47. Shukla, S., Ablack, A. L., Wen, A. M., Lee, K. L., Lewis, J. D., & Steinmetz, N. F. (2013). Increased tumor homing and tissue penetration of the filamentous plant viral nanoparticle potato virus X. Molecular Pharmaceutics, 10(1), 33–42.CrossRefGoogle Scholar
  48. Shukla, S., Eber, F. J., Nagarajan, A. S., DiFranco, N. A., Schmidt, N., Wen, A. M., Eiben, S., Twyman, R. M., Wege, C., & Steinmetz, N. F. (2015). The impact of aspect ratio on the biodistribution and tumor homing of rigid soft-matter nanorods. Advanced Healthcare Materials, 4(6), 874–882.CrossRefGoogle Scholar
  49. Shukla, S., Dorand, R. D., Myers, J. T., Woods, S. E., Gulati, N. M., Stewart, P. L., Commandeur, U., Huang, A. Y., & Steinmetz, N. F. (2016). Multiple administrations of viral nanoparticles alter in vivo behavior—Insights from intravital microscopy. ACS Biomaterials Science & Engineering, 2(5), 829–837.CrossRefGoogle Scholar
  50. Shukla, S., Myers, J. T., Woods, S. E., Gong, X., Czapar, A. E., Commandeur, U., Huang, A. Y., Levine, A. D., & Steinmetz, N. F. (2017). Plant viral nanoparticles-based HER2 vaccine: Immune response influenced by differential transport, localization and cellular interactions of particulate carriers. Biomaterials, 121, 15–27.CrossRefGoogle Scholar
  51. Sonderegger, I., Röhn, T. A., Kurrer, M. O., Iezzi, G., Zou, Y., Kastelein, R. A., Bachmann, M. F., & Kopf, M. (2006). Neutralization of IL-17 by active vaccination inhibits IL-23-dependent autoimmune myocarditis. European Journal of Immunology, 36(11), 2849–2856.CrossRefGoogle Scholar
  52. Spohn, G., Keller, I., Beck, M., Grest, P., Jennings, G. T., & Bachmann, M. F. (2008). Active immunization with IL-1 displayed on virus-like particles protects from autoimmune arthritis. European Journal of Immunology, 38(3), 877–887.CrossRefGoogle Scholar
  53. Tissot, A. C., Maurer, P., Nussberger, J., Sabat, R., Pfister, T., Ignatenko, S., Volk, H.-D., Stocker, H., Müller, P., Jennings, G. T., Wagner, F., & Bachmann, M. F. (2008). Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: A double-blind, randomised, placebo-controlled phase IIa study. The Lancet, 371(9615), 821–827.CrossRefGoogle Scholar
  54. Wang, Q., Lin, T., Johnson, J. E., & Finn, M. G. (2002). Natural supramolecular building blocks. Chemistry & Biology, 9(7), 813–819.CrossRefGoogle Scholar
  55. Wen, A. M., & Steinmetz, N. F. (2014). The aspect ratio of nanoparticle assemblies and the spatial arrangement of ligands can be optimized to enhance the targeting of cancer cells. Advanced Healthcare Materials, 3(11), 1739–1744.CrossRefGoogle Scholar
  56. Wen, A. M., & Steinmetz, N. F. (2016). Design of virus-based nanomaterials for medicine, biotechnology, and energy. Chemical Society Reviews, 45(15), 4074–4126.CrossRefGoogle Scholar
  57. Wen, A. M., Shukla, S., Saxena, P., Aljabali, A. A. A., Yildiz, I., Dey, S., Mealy, J. E., Yang, A. C., Evans, D. J., Lomonossoff, G. P., & Steinmetz, N. F. (2012). Interior engineering of a viral nanoparticle and its tumor homing properties. Biomacromolecules, 13(12), 3990–4001.CrossRefGoogle Scholar
  58. Wen, A. M., Rambhia, P. H., French, R. H., & Steinmetz, N. F. (2013). Design rules for nanomedical engineering: From physical virology to the applications of virus-based materials in medicine. Journal of Biological Physics, 39(2), 301–325.CrossRefGoogle Scholar
  59. Wen, A. M., Le, N., Zhou, X., Steinmetz, N. F., & Popkin, D. L. (2015a). Tropism of CPMV to professional antigen presenting cells enables a platform to eliminate chronic infections. ACS Biomaterials Science & Engineering, 1(11), 1050–1054.CrossRefGoogle Scholar
  60. Wen, A. M., Wang, Y., Jiang, K., Hsu, G. C., Gao, H., Lee, K. L., Yang, A. C., Yu, X., Simon, D. I., & Steinmetz, N. F. (2015b). Shaping bio-inspired nanotechnologies to target thrombosis for dual optical-magnetic resonance imaging. Journal of Materials Chemistry. B, Materials for Biology and Medicine, 3(29), 6037–6045.CrossRefGoogle Scholar
  61. Wen, A. M., Lee, K. L., Cao, P., Pangilinan, K., Carpenter, B. L., Lam, P., Veliz, F. A., Ghiladi, R. A., Advincula, R. C., & Steinmetz, N. F. (2016). Utilizing viral nanoparticle/dendron hybrid conjugates in photodynamic therapy for dual delivery to macrophages and cancer cells. Bioconjugate Chemistry, 27(5), 1227–1235.CrossRefGoogle Scholar
  62. Yildiz, I., Lee, K. L., Chen, K., Shukla, S., & Steinmetz, N. F. (2013). Infusion of imaging and therapeutic molecules into the plant virus-based carrier cowpea mosaic virus: Cargo-loading and delivery. Journal of Controlled Release: Official Journal of the Controlled Release Society, 172(2), 568–578.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Amy M. Wen
    • 1
  • Karin L. Lee
    • 2
  • Nicole F. Steinmetz
    • 3
    Email author
  1. 1.Wyss Institute for Biologically Inspired EngineeringHarvard UniversityBostonUSA
  2. 2.Laboratory of Tumor Immunology and Biology, Center for Cancer ResearchNational Cancer Institute, NIHBethesdaUSA
  3. 3.Department of NanoEngineering, Moores Cancer CenterUniversity of California-San DiegoLa JollaUSA

Personalised recommendations