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Nanotechnology for immuno-oncology

Nature Cancer volume 6, pages 1311–1325 (2025)Cite this article

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Abstract

Although the first generation of cancer immunotherapeutics produced unprecedented improvements in clinical outcomes for individuals with cancer, novel strategies to increase treatment specificity, delivery efficiency and pharmacokinetics are still needed. In this Review, we describe the potential advantages and current limitations of nanomaterials for cancer immunotherapy and highlight rational uses of nanosystems to generate potent and durable antitumor immune responses. We close with a review of the current state of clinical development of nanomedicine for cancer immunotherapy.

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Fig. 1: Advantages of nanomaterials for immunotherapy delivery to tumors and immune cells.
Fig. 2: Nanomaterials for innate immune modulation.
Fig. 3: Nanomaterials for adaptive immune modulation.

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References

  1. Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Pires da Silva, I. et al. Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Lancet Oncol. 22, 836–847 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gettinger, S. N. et al. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer. J. Clin. Oncol. 33, 2004–2012 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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 

  8. Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Gangadhar, T. C. & Vonderheide, R. H. Mitigating the toxic effects of anticancer immunotherapy. Nat. Rev. Clin. Oncol. 11, 91–99 (2014).

    Article  CAS  PubMed  Google Scholar 

  10. Morgan, R. A. et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brentjens, R., Yeh, R., Bernal, Y., Riviere, I. & Sadelain, M. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol. Ther. 18, 666–668 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

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

    Article  CAS  PubMed  Google Scholar 

  15. Li, Y., Kroger, M. & Liu, W. K. Shape effect in cellular uptake of PEGylated nanoparticles: comparison between sphere, rod, cube and disk. Nanoscale 7, 16631–16646 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Dong, S. et al. Adaptive design of mRNA-loaded extracellular vesicles for targeted immunotherapy of cancer. Nat. Commun. 14, 6610 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sayour, E. J., Boczkowski, D., Mitchell, D. A. & Nair, S. K. Cancer mRNA vaccines: clinical advances and future opportunities. Nat. Rev. Clin. Oncol. 21, 489–500 (2024).

  18. Wang, J. et al. Physical activation of innate immunity by spiky particles. Nat. Nanotechnol. 13, 1078–1086 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhu, M. et al. Cell-penetrating nanoparticles activate the inflammasome to enhance antibody production by targeting microtubule-associated protein 1-light chain 3 for degradation. ACS Nano 14, 3703–3717 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sun, B. et al. Engineering an effective immune adjuvant by designed control of shape and crystallinity of aluminum oxyhydroxide nanoparticles. ACS Nano 7, 10834–10849 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mendez-Gomez, H. R. et al. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell 187, 2521–2535 (2024).

  22. Grippin, A. J. et al. Dendritic cell-activating magnetic nanoparticles enable early prediction of antitumor response with magnetic resonance imaging. ACS Nano 13, 13884–13898 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Duan, X. et al. Photodynamic therapy mediated by nontoxic core-shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumor immunity and antimetastatic effect on breast cancer. J. Am. Chem. Soc. 138, 16686–16695 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wan, J., Zhang, X., Tang, D., Liu, T. & Xiao, H. Biodegradable NIR-II pseudo conjugate polymeric nanoparticles amplify photodynamic immunotherapy via alleviation of tumor hypoxia and tumor-associated macrophage reprogramming. Adv. Mater. 35, e2209799 (2023).

    Article  PubMed  Google Scholar 

  25. Hayashi, K. et al. Magnetically responsive smart nanoparticles for cancer treatment with a combination of magnetic hyperthermia and remote-control drug release. Theranostics 4, 834–844 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Marill, J., Mohamed Anesary, N. & Paris, S. DNA damage enhancement by radiotherapy-activated hafnium oxide nanoparticles improves cGAS–STING pathway activation in human colorectal cancer cells. Radiother. Oncol. 141, 262–266 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Bonvalot, S. et al. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 20, 1148–1159 (2019).

    Article  CAS  PubMed  Google Scholar 

  28. Hewitt, S. L. et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Sci. Transl. Med. 11, eaat9143 (2019).

  29. Kang, M. et al. Nanocomplex-mediated in vivo programming to chimeric antigen receptor-M1 macrophages for cancer therapy. Adv. Mater. 33, e2103258 (2021).

    Article  PubMed  Google Scholar 

  30. Chen, C. et al. Intracavity generation of glioma stem cell-specific CAR macrophages primes locoregional immunity for postoperative glioblastoma therapy. Sci. Transl. Med. 14, eabn1128 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Stadler, C. R. et al. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nat. Med. 23, 815–817 (2017).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. Tenchov, R., Bird, R., Curtze, A. E. & Zhou, Q. Lipid nanoparticles from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano 15, 16982–17015 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Liang, Q. et al. The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency. Nat. Biomed. Eng. 3, 729–740 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Guo, P. et al. Nanoparticle elasticity directs tumor uptake. Nat. Commun. 9, 130 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Dane, E. L. et al. STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity. Nat. Mater. 21, 710–720 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen, Y. et al. Therapeutic remodeling of the tumor microenvironment enhances nanoparticle delivery. Adv. Sci. 6, 1802070 (2019).

    Article  Google Scholar 

  40. Wang, Y. et al. Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics. Nat. Nanotechnol. 19, 255–263 (2024).

    Article  CAS  PubMed  Google Scholar 

  41. Schudel, A., Francis, D. M. & Thomas, S. N. Material design for lymph node drug delivery. Nat. Rev. Mater. 4, 415–428 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Galstyan, A. et al. Blood–brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy. Nat. Commun. 10, 3850 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, F. et al. Uniform brain tumor distribution and tumor associated macrophage targeting of systemically administered dendrimers. Biomaterials 52, 507–516 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sayour, E. J. et al. Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles. Oncoimmunology 6, e1256527 (2017).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  46. Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  47. Jneid, B. et al. Selective STING stimulation in dendritic cells primes antitumor T cell responses. Sci. Immunol. 8, eabn6612 (2023).

    Article  CAS  PubMed  Google Scholar 

  48. Yi, S. et al. Tailoring nanostructure morphology for enhanced targeting of dendritic cells in atherosclerosis. ACS Nano 10, 11290–11303 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Karabin, N. B. et al. Sustained micellar delivery via inducible transitions in nanostructure morphology. Nat. Commun. 9, 624 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Si, Y. et al. Adjuvant-free nanofiber vaccine induces in situ lung dendritic cell activation and TH17 responses. Sci. Adv. 6, eaba0995 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sayour, E. J. et al. Personalized tumor RNA loaded lipid-nanoparticles prime the systemic and intratumoral milieu for response to cancer immunotherapy. Nano Lett. 18, 6195–6206 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).

    Article  CAS  PubMed  Google Scholar 

  57. Gainor, J. F. et al. T cell responses to individualized neoantigen therapy mRNA-4157 (V940) alone or in combination with pembrolizumab in the phase 1 KEYNOTE-603 study. Cancer Discov. 14, 2029–2223 (2024).

  58. Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther. 16, 1833–1840 (2008).

    Article  PubMed  Google Scholar 

  59. Carroll, E. C. et al. The vaccine adjuvant chitosan promotes cellular immunity via DNA sensor cGAS–STING-dependent induction of type I interferons. Immunity 44, 597–608 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wegmann, F. et al. Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. Nat. Biotechnol. 30, 883–888 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wei, X. et al. Cationic nanocarriers induce cell necrosis through impairment of Na+/K+-ATPase and cause subsequent inflammatory response. Cell Res. 25, 237–253 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 12, 648–654 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, J. et al. STING licensing of type I dendritic cells potentiates antitumor immunity. Sci. Immunol. 9, eadj3945 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Huang, Z. et al. Anti-tumor immune responses of tumor-associated macrophages via Toll-like receptor 4 triggered by cationic polymers. Biomaterials 34, 746–755 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Marabelle, A., Kohrt, H., Caux, C. & Levy, R. Intratumoral immunization: a new paradigm for cancer therapy. Clin. Cancer Res. 20, 1747–1756 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lu, Y. et al. Immunological conversion of solid tumours using a bispecific nanobioconjugate for cancer immunotherapy. Nat. Nanotechnol. 17, 1332–1341 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shae, D. et al. Endosomolytic polymersomes increase the activity of cyclic dinucleotide STING agonists to enhance cancer immunotherapy. Nat. Nanotechnol. 14, 269–278 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bronte, V. & Murray, P. J. Understanding local macrophage phenotypes in disease: modulating macrophage function to treat cancer. Nat. Med. 21, 117–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  72. Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Samson, N. & Ablasser, A. The cGAS–STING pathway and cancer. Nat. Cancer 3, 1452–1463 (2022).

  74. Li, X. et al. Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles. Nat. Nanotechnol. 17, 891–899 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu, D. et al. Tumor microenvironment-responsive nanoparticles amplifying STING signaling pathway for cancer immunotherapy. Adv. Mater. 36, e2304845 (2024).

    Article  PubMed  Google Scholar 

  76. Wang, X. et al. A protein-based cGAS–STING nanoagonist enhances T cell-mediated anti-tumor immune responses. Nat. Commun. 13, 5685 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rodell, C. B. et al. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2, 578–588 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Tahtinen, S. et al. IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nat. Immunol. 23, 532–542 (2022).

    Article  CAS  PubMed  Google Scholar 

  79. Feng, M. et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat. Rev. Cancer 19, 568–586 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. von Roemeling, C. A. et al. Therapeutic modulation of phagocytosis in glioblastoma can activate both innate and adaptive antitumour immunity. Nat. Commun. 11, 1508 (2020).

    Article  Google Scholar 

  81. Koh, E. et al. Exosome-SIRPα, a CD47 blockade increases cancer cell phagocytosis. Biomaterials 121, 121–129 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Lee, N. K. et al. Caspase-cleavable peptide–doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer. Biomaterials 277, 121105 (2021).

    Article  CAS  PubMed  Google Scholar 

  83. Kulkarni, A. et al. A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nat. Biomed. Eng. 2, 589–599 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Barkal, A. A. et al. CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy. Nature 572, 392–396 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yuan, H. et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nat. Nanotechnol. 12, 763–769 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Lei, A. et al. A second-generation M1-polarized CAR macrophage with antitumor efficacy. Nat. Immunol. 25, 102–116 (2024).

    Article  CAS  PubMed  Google Scholar 

  87. Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Sloas, C. et al. Macrophages expressing synthetic cytokine receptors reverse IL10-mediated immunosuppression within solid tumors and promote adaptive immunity. Cancer Res. 84, 5249 (2024).

    Article  Google Scholar 

  89. Kim, K. S. et al. Cationic nanoparticle-mediated activation of natural killer cells for effective cancer immunotherapy. ACS Appl. Mater. Interfaces 12, 56731–56740 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Shin, H. et al. Enhancing CAR-NK cells against solid tumors through chemical and genetic fortification with DOTAP-functionalized lipid nanoparticles. Adv. Funct. Mater. 34, 2315721 (2024).

  91. Myers, J. A. & Miller, J. S. Exploring the NK cell platform for cancer immunotherapy. Nat. Rev. Clin. Oncol. 18, 85–100 (2021).

    Article  PubMed  Google Scholar 

  92. Au, K. M., Park, S. I. & Wang, A. Z. Trispecific natural killer cell nanoengagers for targeted chemoimmunotherapy. Sci. Adv. 6, eaba8564 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang, D. Y. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 4, 1721–1728 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Johnson, D. B., Nebhan, C. A., Moslehi, J. J. & Balko, J. M. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat. Rev. Clin. Oncol. 19, 254–267 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat. Rev. 44, 51–60 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).

    Article  PubMed  Google Scholar 

  100. June, C. H., Riddell, S. R. & Schumacher, T. N. Adoptive cellular therapy: a race to the finish line. Sci. Transl. Med. 7, 280ps287 (2015).

    Article  Google Scholar 

  101. Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Larson, R. C. & Maus, M. V. Recent advances and discoveries in the mechanisms and functions of CAR T cells. Nat. Rev. Cancer 21, 145–161 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Maggs, L., Cattaneo, G., Dal, A. E., Moghaddam, A. S. & Ferrone, S. CAR T cell-based immunotherapy for the treatment of glioblastoma. Front. Neurosci. 15, 662064 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Imai, C. et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18, 676–684 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Krause, A. et al. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J. Exp. Med. 188, 619–626 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. van der Stegen, S. J., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Guo, Y. et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat. Immunol. 22, 746–756 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Zhu, C. et al. Injectable supramolecular hydrogels for in situ programming of CAR-T cells toward solid tumor immunotherapy. Adv. Mater. 36, e2310078 (2024).

    Article  PubMed  Google Scholar 

  112. Verdun, N. & Marks, P. Secondary cancers after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 390, 584–586 (2024).

    Article  CAS  PubMed  Google Scholar 

  113. Billingsley, M. M. et al. Ionizable lipid nanoparticle-mediated mRNA delivery for human CAR T cell engineering. Nano Lett. 20, 1578–1589 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Parayath, N. N., Stephan, S. B., Koehne, A. L., Nelson, P. S. & Stephan, M. T. In vitro-transcribed antigen receptor mRNA nanocarriers for transient expression in circulating T cells in vivo. Nat. Commun. 11, 6080 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mabry, R. et al. 1222 In situ CAR therapy using oRNA lipid nanoparticles regresses tumors in mice. J. Immunother. Cancer 10, A1265 (2022).

    Google Scholar 

  116. Tombacz, I. et al. Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA–LNPs. Mol. Ther. 29, 3293–3304 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Haist, M., Mailander, V. & Bros, M. Nanodrugs targeting T cells in tumor therapy. Front. Immunol. 13, 912594 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).

    Article  PubMed  Google Scholar 

  119. Park, J. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 11, 895–905 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1747 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Shi, C. et al. Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics. Nat. Nanotechnol. 18, 86–97 (2023).

    Article  CAS  PubMed  Google Scholar 

  122. Jiang, C.-T. et al. Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy. Nat. Commun. 12, 1359 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Alhallak, K. et al. Nanoparticle T-cell engagers as a modular platform for cancer immunotherapy. Leukemia 35, 2346–2357 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang, D. et al. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat. Nanotechnol. 17, 777–787 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hu, X. et al. An artificial metabzyme for tumour-cell-specific metabolic therapy. Nat. Nanotechnol. 19, 1712–1722 (2024).

  126. Li, S. et al. Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat. Biomed. Eng. 5, 455–466 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sun, X. et al. Amplifying STING activation by cyclic dinucleotide–manganese particles for local and systemic cancer metalloimmunotherapy. Nat. Nanotechnol. 16, 1260–1270 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wang, Y. et al. Universal STING mimic boosts antitumour immunity via preferential activation of tumour control signalling pathways. Nat. Nanotechnol. 19, 856–866 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Powderly, J. D. et al. Phase 1/2 study of mRNA-4359 administered alone and in combination with immune checkpoint blockade in adult participants with advanced solid tumors. J. Clin. Oncol. 41, TPS2676 (2023).

    Article  Google Scholar 

  130. Sethna, Z. et al. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer. Nature 639, 1042–1051 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lopez, J. et al. Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial. Nat. Med. 31, 152–164 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Guan, C. et al. RNA-based immunostimulatory liposomal spherical nucleic acids as potent TLR7/8 modulators. Small 14, e1803284 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Daniel, W. L., Lorch, U., Mix, S. & Bexon, A. S. A first-in-human phase 1 study of cavrotolimod, a TLR9 agonist spherical nucleic acid, in healthy participants: evidence of immune activation. Front. Immunol. 13, 1073777 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Duurland, C. L. et al. INT-1B3, an LNP formulated miR-193a-3p mimic, promotes anti-tumor immunity by enhancing T cell mediated immune responses via modulation of the tumor microenvironment and induction of immunogenic cell death. Oncotarget 15, 470–485 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Jang, S. C. et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun. Biol. 4, 497 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Waldron, J. Codiak files for bankruptcy after exosome-focused biotech unable to satisfy ‘financial needs’. Fierce Biotech (27 March 2023).

  137. Diab, A. et al. Bempegaldesleukin plus nivolumab in untreated advanced melanoma: the open-label, phase III PIVOT IO 001 trial results. J. Clin. Oncol. 41, 4756–4767 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Diab, A. et al. PIVOT IO 001: first disclosure of efficacy and safety of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) vs NIVO monotherapy in advanced melanoma (MEL). Ann. Oncol. 33, S901 (2022).

    Article  Google Scholar 

  139. Diab, A. et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov. 10, 1158–1173 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Diab, A. et al. Immune monitoring after NKTR-214 plus nivolumab (PIVOT-02) in previously untreated patients with metastatic stage IV melanoma. J. Transl. Med. 17 (2019).

  141. Diab, A. et al. Bempegaldesleukin plus nivolumab in first-line metastatic melanoma. J. Clin. Oncol. 39, 2914–2925 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Alvarez, R. D. et al. A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG–PEI–cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol. Oncol. 133, 433–438 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Stadler, C. R. et al. Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6. Sci. Transl. Med. 16, eadl2720 (2024).

    Article  CAS  PubMed  Google Scholar 

  144. Le, N. T. A phase I study to evaluate the safety and tolerability of JCXH-211 (a self-replicating mRNA encoding IL-12) intratumoral injection in patients with malignant solid tumors: results from the phase Ia dose escalation. J. Clin. Oncol. 42, 2539 (2024).

  145. Wang, Z. H. et al. Intravenous administration of IL-12 encoding self-replicating RNA–lipid nanoparticle complex leads to safe and effective antitumor responses. Sci. Rep. 14, 7366 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Patel, M. et al. 539 Phase 1 study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L/IL-23/IL-36γ, for intratumoral (ITu) injection ± durvalumab in advanced solid tumors and lymphoma. J. ImmunoTher. Cancer 9, A569 (2021).

    Google Scholar 

  147. Moderna R&D Day highlights progress and strategic priorities; https://investors.modernatx.com/news/news-details/2024/Moderna-RD-Day-Highlights-Progress-and-Strategic-Priorities/default.aspx (2024).

  148. Bentebibel, S. E. et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL-2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 9, 711–721 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Hamilton, E. et al. 801 PRIME IL-15 (RPTR-147): preliminary clinical results and biomarker analysis from a first-in-human phase 1 study of IL-15 loaded peripherally-derived autologous T cell therapy in solid tumor patients. J. ImmunoTher. Cancer 8, A479–A480 (2020).

    Google Scholar 

  150. Haanen, J. 611O. Updated results from BNT211-01 (NCT04503278), an ongoing, first-in-human, phase 1 study evaluating safety and efficacy of CLDN6 CAR T cells and a CLDN6-encoding mRNA vaccine in patients with relapsed/refractory CLDN6+ solid tumors. Ann. Oncol. 35, S489–S490 (2024).

    Article  Google Scholar 

  151. MacDiarmid, J. A. et al. Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug. Nat. Biotechnol. 27, 643–651 (2009).

    Article  CAS  PubMed  Google Scholar 

  152. van Zandwijk, N. et al. Safety and activity of microRNA-loaded minicells in patients with recurrent malignant pleural mesothelioma: a first-in-man, phase 1, open-label, dose-escalation study. Lancet Oncol. 18, 1386–1396 (2017).

    Article  PubMed  Google Scholar 

  153. Ganju, V. et al. Phase I/IIa trial in advanced pancreatic ductal adenocarcinoma treated with cytotoxic drug-packaged, EGFR-targeted nanocells and glycolipid-packaged nanocells. Clin. Cancer Res. 30, 304–314 (2024).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  155. Albanese, A., Tang, P. S. & Chan, W. C. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu. Rev. Biomed. Eng. 14, 1–16 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Grippin, A. J., Sayour, E. J. & Mitchell, D. A. Translational nanoparticle engineering for cancer vaccines. Oncoimmunology 6, e1290036 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Mulhopt, S. et al. Characterization of nanoparticle batch-to-batch variability. Nanomaterials 8, 311 (2018).

  160. Kurzrock, R. et al. Moving beyond 3 + 3: the future of clinical trial design. Am. Soc. Clin. Oncol. Educ. Book 41, e133–e144 (2021).

    Article  PubMed  Google Scholar 

  161. McQuade, J. L., Daniel, C. R., Helmink, B. A. & Wargo, J. A. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol. 20, e77–e91 (2019).

    Article  PubMed  Google Scholar 

  162. Rosshart, S. P. et al. Laboratory mice born to wild mice have natural microbiota and model human immune responses. Science 365, eaaq4361 (2019).

  163. Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lei, K. et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat. Biomed. Eng. 5, 1411–1425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Fuhs, T. et al. Rigid tumours contain soft cancer cells. Nat. Phys. 18, 1510–1519 (2022).

  166. Sceneay, J. et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 9, 1208–1227 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Conforti, F. et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 19, 737–746 (2018).

    Article  CAS  PubMed  Google Scholar 

  168. Serpooshan, V. et al. Effect of cell sex on uptake of nanoparticles: the overlooked factor at the nanobio interface. ACS Nano 12, 2253–2266 (2018).

    Article  CAS  PubMed  Google Scholar 

  169. Kim, J., Eygeris, Y., Gupta, M. & Sahay, G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 170, 83–112 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Wittrup, A. et al. Visualizing lipid-formulated siRNA release from endosomes and target gene knockdown. Nat. Biotechnol. 33, 870–876 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. F. Wogan of the Division of Radiation Oncology at MD Anderson Cancer Center for editing this manuscript. This work is supported, in part, by National Institutes of Health grants R01CA291876, R01CA284108, R01NS117828 and T32-CA196561-08, American Cancer Society grant RSG-22-052-01-IBCD, Cancer Prevention and Research Institute of Texas grants RP240493 and RP250191, the American Brain Tumor Association, the Radiological Society of North America, the Red Gates Foundation and Colorectal Cancer Alliance. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.

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  1. These authors contributed equally: Adam J. Grippin, DaeYong Lee.

Authors and Affiliations

  1. Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Adam J. Grippin & Wen Jiang

  2. Fralin Biomedical Research Institute at VTC, Virginia Tech, Roanoke, VA, USA

    DaeYong Lee

  3. Department of Biomedical Engineering, Virginia Tech, Blacksburg, VA, USA

    DaeYong Lee

  4. Department of Oncology, Oxford University, Oxford, UK

    Eileen E. Parkes

  5. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Betty Y. S. Kim

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  4. Wen Jiang
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Contributions

A.J.G., W.J. and B.Y.S.K. conceived the project and were responsible for all phases of manuscript preparation. A.J.G., D.L., W.J. and B.Y.S.K. wrote the manuscript. A.G. and D.L. designed the figures. All authors searched for literature and edited the manuscript.

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

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Grippin, A.J., Lee, D., Parkes, E.E. et al. Nanotechnology for immuno-oncology. Nat Cancer 6, 1311–1325 (2025). https://doi.org/10.1038/s43018-025-01025-x

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