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Nature Biotechnology·· 1 天前AI 评分52

可编程 mRNA 疫苗材料实现抗肿瘤免疫的时间调控

Programmable mRNA vaccine materials for temporal control of antitumour immunity

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Nature Biotechnology 刊出综述《Programmable mRNA vaccine materials for temporal control of antitumour immunity》,讨论通过材料设计在时间维度调控 mRNA 疫苗激发的抗肿瘤免疫。

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  1. Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Shi, Y. et al. Chemically modified platforms for better RNA therapeutics. Chem. Rev. 124, 929–1033 (2024).

    CAS  PubMed  Google Scholar 

  3. Barbier, A. J., Jiang, A. Y., Zhang, P., Wooster, R. & Anderson, D. G. The clinical progress of mRNA vaccines and immunotherapies. Nat. Biotechnol. 40, 840–854 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    Article  PubMed  Google Scholar 

  5. Yaremenko, A. V., Khan, M. M., Zhen, X., Tang, Y. & Tao, W. Clinical advances of mRNA vaccines for cancer immunotherapy. Med 6, 100562 (2025).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. 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 

  9. Sahin, U. et al. Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC. Nature 651, 1088–1096 (2026).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  PubMed  Google Scholar 

  11. Khattak, A. et al. Intismeran autogene plus pembrolizumab versus pembrolizumab alone in high-risk resected melanoma: 5-year update of the randomized phase 2b KEYNOTE-942 study. J. Clin. Oncol. https://doi.org/10.1200/JCO-1226-00835 (2026).

    Article  PubMed  Google Scholar 

  12. Peng, K., Zhao, X., Fu, Y.-X. & Liang, Y. Eliciting antitumor immunity via therapeutic cancer vaccines. Cell. Mol. Immunol. 22, 840–868 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vu, T. et al. BCMA-directed mRNA CAR T cell therapy for myasthenia gravis: a randomized, double-blind, placebo-controlled phase 2b trial. Nat. Med. 32, 1131–1141 (2026).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hunter, T. L. et al. In vivo CAR T cell generation to treat cancer and autoimmune disease. Science 388, 1311–1317 (2025).

    CAS  PubMed  Google Scholar 

  15. Wang, Q. et al. In vivo CD19 CAR T-cell therapy for refractory systemic lupus erythematosus. N. Engl. J. Med. 393, 1542–1544 (2025).

    PubMed  Google Scholar 

  16. Bot, A. et al. In vivo chimeric antigen receptor (CAR)-T cell therapy. Nat. Rev. Drug Discov. 25, 116–137 (2026).

    Article  CAS  PubMed  Google Scholar 

  17. Martini, D. J. & Wu, C. J. The future of personalized cancer vaccines. Cancer Discov. 15, 1315–1324 (2025).

    CAS  PubMed  Google Scholar 

  18. Lorentzen, C. L., Haanen, J. B., Met, Ö & Svane, I. M. Clinical advances and ongoing trials of mRNA vaccines for cancer treatment. Lancet Oncol. 23, e450–e458 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lang, F., Schrörs, B., Löwer, M., Türeci, Ö & Sahin, U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat. Rev. Drug Discov. 21, 261–282 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Horowitz, M., Neeman, E., Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat. Rev. Clin. Oncol. 12, 213–226 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Park, C. G. et al. Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. Sci. Transl. Med. 10, eaar1916 (2018).

    PubMed  Google Scholar 

  22. Bakos, O., Lawson, C., Rouleau, S. & Tai, L.-H. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J. Immunother. Cancer 6, 86 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. Bezu, L. et al. Perioperative immunosuppressive factors during cancer surgery: an updated review. Cancers 16, 2304 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Krall, J. A. et al. The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Sci. Transl. Med. 10, eaan3464 (2018).

    PubMed  PubMed Central  Google Scholar 

  25. Cheng, X., Zhang, H., Hamad, A., Huang, H. & Tsung, A. in Seminars in Cancer Biology 408–419 (Elsevier).

  26. Chen, S. et al. Nanotechnology-based mRNA vaccines. Nat. Rev. Methods Primers 3, 63 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Palmer, C. D. et al. Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 28, 1619–1629 (2022).

    Article  CAS  PubMed  Google Scholar 

  29. Pittet, M. J., Di Pilato, M., Garris, C. & Mempel, T. R. Dendritic cells as shepherds of T cell immunity in cancer. Immunity 56, 2218–2230 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Duong, E. et al. Type I interferon activates MHC class I-dressed CD11b+ conventional dendritic cells to promote protective anti-tumor CD8+ T cell immunity. Immunity 55, 308–323.e309 (2022).

    CAS  PubMed  Google Scholar 

  31. Karikó, K., Buckstein, M., Ni, H. & Weissman, D. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23, 165–175 (2005).

    PubMed  Google Scholar 

  32. Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Anderson, B. R. et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic acids Res. 38, 5884–5892 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. McGee, J. E. et al. Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency. Nat. Biotechnol. 43, 720–726 (2025).

    Article  CAS  PubMed  Google Scholar 

  35. Chaudhary, N., Weissman, D. & Whitehead, K. A. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat. Rev. Drug Discov. 20, 817–838 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Von Niessen, A. G. O. et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019).

    Google Scholar 

  37. Farzani, T. et al. A modular mRNA–LNP vaccine platform enables integrated RNA, lipid and antigen design to protect against CCHFV. Preprint at bioRxiv https://doi.org/10.64898/2026.01.17.699915 (2026).

  38. Medjmedj, A. et al. Evaluation of synthetic mRNA with selected UTR sequences and alternative poly (A) tail, in vitro and in vivo. Mol. Ther. Nucleic Acids 36, 102648 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. West, J. D. et al. The quantitative impact of 3′ UTRs on gene expression. Nucleic Acids Res. 53, gkaf568 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).

    Article  CAS  PubMed  Google Scholar 

  41. Wesselhoeft, R. A., Kowalski, P. S. & Anderson, D. G. Engineering circular RNA for potent and stable translation in eukaryotic cells. Nat. Commun. 9, 2629 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dailey, G. P., Crosby, E. J. & Hartman, Z. C. Cancer vaccine strategies using self-replicating RNA viral platforms. Cancer Gene Ther. 30, 794–802 (2023).

    Article  CAS  PubMed  Google Scholar 

  43. Morse, M. A. et al. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Ther. 30, 803–811 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. Nanotechnol. 15, 313–320 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

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

    Article  CAS  PubMed  Google Scholar 

  47. Voke, E. et al. Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo. Nat. Commun. 16, 8699 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sabnis, S. et al. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 26, 1509–1519 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Xue, L. et al. Combinatorial design of siloxane-incorporated lipid nanoparticles augments intracellular processing for tissue-specific mRNA therapeutic delivery. Nat. Nanotechnol. 20, 132–143 (2025).

    Article  CAS  PubMed  Google Scholar 

  50. Chaudhary, N. et al. Amine headgroups in ionizable lipids drive immune responses to lipid nanoparticles by binding to the receptors TLR4 and CD1d. Nat. Biomed. Eng. 8, 1483–1498 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kim, B. et al. Targeted suppression of type 1 interferon signaling during RNA delivery enhances vaccine-elicited immunity. Preprint at bioRxiv https://doi.org/10.1101/2025.03.09.642244 (2025).

  52. Ripoll, M. et al. An imidazole modified lipid confers enhanced mRNA-LNP stability and strong immunization properties in mice and non-human primates. Biomaterials 286, 121570 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 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 

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

    Article  CAS  PubMed  Google Scholar 

  55. Lee, Y., Jeong, M., Park, J., Jung, H. & Lee, H. Immunogenicity of lipid nanoparticles and its impact on the efficacy of mRNA vaccines and therapeutics. Exp. Mol. Med. 55, 2085–2096 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Luo, Z. et al. Spleen-targeted mRNA vaccine doped with manganese adjuvant for robust anticancer immunity in vivo. ACS Nano 18, 30701–30715 (2024).

    CAS  PubMed  Google Scholar 

  58. Budczies, J. et al. Tumour mutational burden: clinical utility, challenges and emerging improvements. Nat. Rev. Clin. Oncol. 21, 725–742 (2024).

    Article  PubMed  Google Scholar 

  59. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Katsikis, P. D., Ishii, K. J. & Schliehe, C. Challenges in developing personalized neoantigen cancer vaccines. Nat. Rev. Immunol. 24, 213–227 (2024).

    Article  CAS  PubMed  Google Scholar 

  61. Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Wainberg, Z. A. et al. Lymph node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: phase 1 AMPLIFY-201 trial final results. Nat. Med. 31, 3648–3653 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Elicio Therapeutics. Elicio Therapeutics Reports Results from Phase 2 AMPLIFY-7P Study and Outlines Refined Phase 3 Development Strategy for ELI-002 7P in Adjuvant Pancreatic Cancer. https://elicio.com/press_releases/elicio-therapeutics-reports-results-from-phase-2-amplify-7p-study-and-outlines-refined-phase-3-development-strategy-for-eli-002-7p-in-adjuvant-pancreatic-cancer/ (2026).

  64. Chow, A., Perica, K., Klebanoff, C. A. & Wolchok, J. D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 19, 775–790 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  65. De Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    PubMed  Google Scholar 

  66. Kirtane, K., Elmariah, H., Chung, C. H. & Abate-Daga, D. Adoptive cellular therapy in solid tumor malignancies: review of the literature and challenges ahead. J. Immunother. Cancer 9, e002723 (2021).

    PubMed  PubMed Central  Google Scholar 

  67. Escobar, G., Berger, T. R. & Maus, M. V. CAR-T cells in solid tumors: challenges and breakthroughs. Cell Rep. Med. 6, 102353 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Fan, T. et al. Therapeutic cancer vaccines: advancements, challenges and prospects. Signal Transduct. Target. Ther. 8, 450 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Grippin, A. J. et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature 647, 488–497 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  PubMed  Google Scholar 

  71. Hotz, C. et al. Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models. Sci. Transl. Med. 13, eabc7804 (2021).

    CAS  PubMed  Google Scholar 

  72. Hamouda, A. E. et al. Intratumoral delivery of lipid nanoparticle-formulated mRNA encoding IL-21, IL-7, and 4-1BBL induces systemic anti-tumor immunity. Nat. Commun. 15, 10635 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bain, C., Myles, P., Corcoran, T. & Dieleman, J. M. Postoperative systemic inflammatory dysregulation and corticosteroids: a narrative review. Anaesthesia 78, 356–370 (2023).

    CAS  PubMed  Google Scholar 

  74. Allen, J. E. IL-4 and IL-13: regulators and effectors of wound repair. Annu. Rev. Immunol. 41, 229–254 (2023).

    CAS  PubMed  Google Scholar 

  75. Topalian, S. L., Taube, J. M. & Pardoll, D. M. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367, eaax0182 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Delclaux, I., Ventre, K. S., Jones, D. & Lund, A. W. The tumor-draining lymph node as a reservoir for systemic immune surveillance. Trends Cancer 10, 28–37 (2024).

    CAS  PubMed  Google Scholar 

  77. Lee, A. H. et al. Neoadjuvant PD-1 blockade induces T cell and cDC1 activation but fails to overcome the immunosuppressive tumor associated macrophages in recurrent glioblastoma. Nat. Commun. 12, 6938 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Forde, P. M. et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N. Engl. J. Med. 386, 1973–1985 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Forde, P. M. et al. Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. N. Engl. J. Med. 393, 741–752 (2025).

    CAS  PubMed  Google Scholar 

  81. Lei, J. et al. Development of mannosylated lipid nanoparticles for mRNA cancer vaccine with high antigen presentation efficiency and immunomodulatory capability. Angew. Chem. 136, e202318515 (2024).

    Google Scholar 

  82. Hamilton, A. G. et al. High-throughput in vivo screening identifies differential influences on mRNA lipid nanoparticle immune cell delivery by administration route. ACS Nano 18, 16151–16165 (2024).

    CAS  PubMed  Google Scholar 

  83. van den Berg, A. I., Yun, C.-O., Schiffelers, R. M. & Hennink, W. E. Polymeric delivery systems for nucleic acid therapeutics: approaching the clinic. J. Controlled Rel. 331, 121–141 (2021).

    Google Scholar 

  84. De Coen, R. et al. Next-generation bio-reducible lipids enable enhanced vaccine efficacy in malaria and primate models. Adv. Funct. Mater. 36, e09838 (2026).

    Google Scholar 

  85. Hatit, M. Z. et al. Species-dependent in vivo mRNA delivery and cellular responses to nanoparticles. Nat. Nanotechnol. 17, 310–318 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Controlled Rel. 217, 345–351 (2015).

    CAS  Google Scholar 

  87. Hassett, K. J. et al. mRNA vaccine trafficking and resulting protein expression after intramuscular administration. Mol. Ther. Nucleic Acids 35, 102083 (2024).

    CAS  PubMed  Google Scholar 

  88. Buckley, M. et al. Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates. Mol. Ther. 33, 1105–1117 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kim, S. et al. Innate immune responses against mRNA vaccine promote cellular immunity through IFN-β at the injection site. Nat. Commun. 15, 7226 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dowell, W. et al. Distinct inflammatory programs underlie the intramuscular lipid nanoparticle response. ACS Nano 18, 33058–33072 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Ren, Y. et al. Impact of ionizable lipid type on the pharmacokinetics and biodistribution of mRNA-lipid nanoparticles after intravenous and subcutaneous injection. J. Controlled Rel. 384, 113945 (2025).

    CAS  Google Scholar 

  92. Hosseini-Kharat, M., Bremmell, K. E. & Prestidge, C. A. Why do lipid nanoparticles target the liver? Understanding of biodistribution and liver-specific tropism. Mol. Ther. Methods Clin. Dev. 33, 101436 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang, T. et al. Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo. iScience 27, 109804 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Shi, Y. et al. Structural and biochemical characteristics of mRNA nanoparticles determine anti–SARS-CoV-2 humoral and cellular immune responses. Sci. Adv. 8, eabo1827 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. LoPresti, S. T., Arral, M. L., Chaudhary, N. & Whitehead, K. A. The replacement of helper lipids with charged alternatives in lipid nanoparticles facilitates targeted mRNA delivery to the spleen and lungs. J. Controlled Rel. 345, 819–831 (2022).

    CAS  Google Scholar 

  96. Hassett, K. J. et al. Impact of lipid nanoparticle size on mRNA vaccine immunogenicity. J. Controlled Rel. 335, 237–246 (2021).

    CAS  Google Scholar 

  97. Okuda, K. et al. On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device. J. Controlled Rel. 348, 648–659 (2022).

    CAS  Google Scholar 

  98. Suk, J. S., Xu, Q., Kim, N., Hanes, J. & Ensign, L. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery. Adv. Drug Deliv. Rev. 99, 28–51 (2016).

    CAS  PubMed  Google Scholar 

  99. Kawaguchi, Y. et al. Modulating immunogenicity and reactogenicity in mRNA-lipid nanoparticle vaccines through lipid component optimization. ACS Nano 19, 27977–28001 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Zalba, S., Ten Hagen, T. L., Burgui, C. & Garrido, M. J. Stealth nanoparticles in oncology: facing the PEG dilemma. J. Controlled Rel. 351, 22–36 (2022).

    CAS  Google Scholar 

  101. Ibrahim, M. et al. Polyethylene glycol (PEG): the nature, immunogenicity, and role in the hypersensitivity of PEGylated products. J. Controlled Rel. 351, 215–230 (2022).

    CAS  Google Scholar 

  102. Francia, V., Schiffelers, R. M., Cullis, P. R. & Witzigmann, D. The biomolecular corona of lipid nanoparticles for gene therapy. Bioconjugate Chem. 31, 2046–2059 (2020).

    CAS  Google Scholar 

  103. van Straten, D. et al. Biofluid specific protein coronas affect lipid nanoparticle behavior in vitro. J. Controlled Rel. 373, 481–492 (2024).

    Google Scholar 

  104. Sharma, P., Hoorn, D., Aitha, A., Breier, D. & Peer, D. The immunostimulatory nature of mRNA lipid nanoparticles. Adv. Drug Deliv. Rev. 205, 115175 (2024).

    CAS  PubMed  Google Scholar 

  105. Zhao, S. et al. Acid-degradable lipid nanoparticles enhance the delivery of mRNA. Nat. Nanotechnol. 19, 1702–1711 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Chen, Z. et al. Modular design of biodegradable ionizable lipids for improved mRNA delivery and precise cancer metastasis delineation in vivo. J. Am. Chem. Soc. 145, 24302–24314 (2023).

    CAS  PubMed  Google Scholar 

  108. Jörgensen, A. M., Wibel, R. & Bernkop-Schnürch, A. Biodegradable cationic and ionizable cationic lipids: a roadmap for safer pharmaceutical excipients. Small 19, 2206968 (2023).

    Google Scholar 

  109. Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).

    Article  CAS  PubMed  Google Scholar 

  110. Paramasivam, P. et al. Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale. J. Cell Biol. 221, e202110137 (2021).

    PubMed  PubMed Central  Google Scholar 

  111. Philipp, J. et al. pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function. Proc. Natl Acad. Sci. USA 120, e2310491120 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Forster, J. III, Nandi, D. & Kulkarni, A. mRNA-carrying lipid nanoparticles that induce lysosomal rupture activate NLRP3 inflammasome and reduce mRNA transfection efficiency. Biomater. Sci. 10, 5566–5582 (2022).

    Google Scholar 

  113. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Arunachalam, P. S. et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature 596, 410–416 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yamaguchi, Y. et al. Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells. JCI Insight 7, e163347 (2022).

    PubMed  PubMed Central  Google Scholar 

  116. Li, S., Zou, Y., McMasters, A., Chen, F. & Yan, J. Trained immunity: a new player in cancer immunotherapy. eLife 14, e104920 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Sui, Y. & Berzofsky, J. A. Trained immunity inducers in cancer immunotherapy. Front. Immunol. 15, 1427443 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kaech, S. M., Wherry, E. J. & Ahmed, R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol. 2, 251–262 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Dafflisio, G. J. et al. Time to treatment initiation for the 30 most prevalent cancer types: trends and predictors of change. JCO Oncol. Pract. 22, 141–150 (2026).

    PubMed  Google Scholar 

  120. Baranowski, M. L., Yeung, H., Chen, S. C., Gillespie, T. W. & Goodman, M. Factors associated with time to surgery in melanoma: an analysis of the national cancer database. J. Am. Acad. Dermatol. 81, 908–916 (2019).

    PubMed  PubMed Central  Google Scholar 

  121. Wiener, A. A. et al. Reexamining time from breast cancer diagnosis to primary breast surgery. JAMA Surg. 158, 485–492 (2023).

    PubMed  PubMed Central  Google Scholar 

  122. Kovacevic, B., Ewertsen, C., Kristensen, T. S., Penninga, L. & Hansen, C. P. Progression of resectable pancreatic ductal adenocarcinoma during surgical delay and effects on survival — a propensity score matched study. Pancreatology 25, 228–233 (2025).

    PubMed  Google Scholar 

  123. Perez, C. et al. Wait times between lung cancer diagnosis and surgery: national trends, disparities, and impact on long-term survival. J. Thorac. Dis. 17, 5983–5992 (2025).

    PubMed  PubMed Central  Google Scholar 

  124. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    CAS  PubMed  Google Scholar 

  125. Coulie, P. G., Van den Eynde, B. J., Van Der Bruggen, P. & Boon, T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat. Rev. Cancer 14, 135–146 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 21, 485–498 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sittplangkoon, C. et al. mRNA vaccine with unmodified uridine induces robust type I interferon-dependent anti-tumor immunity in a melanoma model. Front. Immunol. 13, 983000 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Qdaisat, S. et al. Sensitization of tumours to immunotherapy by boosting early type-I interferon responses enables epitope spreading. Nat. Biomed. Eng. 9, 1437–1452 (2025).

    Article  CAS  PubMed  Google Scholar 

  133. Zhang, M. et al. STING-activating polymers boost lymphatic delivery of mRNA vaccine to potentiate cancer immunotherapy. Adv. Mater. 37, 2412654 (2025).

    CAS  Google Scholar 

  134. Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Hiller, J. G., Perry, N. J., Poulogiannis, G., Riedel, B. & Sloan, E. K. Perioperative events influence cancer recurrence risk after surgery. Nat. Rev. Clin. Oncol. 15, 205–218 (2018).

    Article  PubMed  Google Scholar 

  136. Xie, N. et al. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target. Ther. 8, 9 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Monroe, J. et al. N1-methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation. Nat. Commun. 15, 8119 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chen, H. et al. Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation. Nat. Biotechnol. 43, 1128–1143 (2025).

    Article  CAS  PubMed  Google Scholar 

  139. Castillo-Hair, S. et al. Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning. Nat. Commun. 15, 5284 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Zhang, H. et al. Deep generative models design mRNA sequences with enhanced translational capacity and stability. Science 390, eadr8470 (2025).

    CAS  PubMed  Google Scholar 

  141. Li, Y. et al. Deep generative optimization of mRNA codon sequences for enhanced mRNA translation and therapeutic efficacy. Nat. Commun. 16, 9957 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Spiewla, T. et al. PolyA tail segmentation improves the stability of the template DNA and increases the translatability of in vitro transcribed mRNA. Nucleic Acids Res. 54, gkaf1412 (2026).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Du, Y. et al. Efficient circular RNA synthesis for potent rolling circle translation. Nat. Biomed. Eng. 9, 1062–1074 (2025).

    Article  CAS  PubMed  Google Scholar 

  144. Fukuchi, K. et al. Internal cap-initiated translation for efficient protein production from circular mRNA. Nat. Biotechnol. 44, 120–132 (2025).

    Article  PubMed  Google Scholar 

  145. Feng, Y. et al. Albumin-recruiting lipid nanoparticle potentiates the safety and efficacy of mRNA vaccines by avoiding liver accumulation. Nat. Mater. 24, 1826–1839 (2025).

    Article  CAS  PubMed  Google Scholar 

  146. Guo, C. et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature 620, 200–208 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Meiser, P. et al. A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity. Cancer Cell 41, 1498–1515.e10 (2023).

    CAS  PubMed  Google Scholar 

  148. Lei, X. et al. CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment. Nat. Commun. 14, 217 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. npj Vaccines 4, 7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).

    Article  CAS  PubMed  Google Scholar 

  151. Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Fan, T. et al. Lipopolyplex-formulated mRNA cancer vaccine elicits strong neoantigen-specific T cell responses and antitumor activity. Sci. Adv. 10, eadn9961 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Garris, C. S. et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity 49, 1148–1161.e7 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Yi, M. et al. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct. Target. Ther. 9, 176 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Del Prete, A. et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell. Mol. Immunol. 20, 432–447 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Tregoning, J. S., Wang, Z., Sridhar, S., Shattock, R. J. & DeRosa, F. Immunology of RNA-based vaccines: the critical interplay between inflammation and expression. Mol. Ther. 33, 5945–5964 (2025).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Lee, J., Woodruff, M. C., Kim, E. H. & Nam, J.-H. Knife’s edge: balancing immunogenicity and reactogenicity in mRNA vaccines. Exp. Mol. Med. 55, 1305–1313 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Li, B. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).

    Article  CAS  PubMed  Google Scholar 

  159. Xu, Y. et al. AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery. Nat. Commun. 15, 6305 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Witten, J. et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. 43, 1790–1799 (2025).

    Article  CAS  PubMed  Google Scholar 

  161. Wang, W. et al. Artificial intelligence-driven rational design of ionizable lipids for mRNA delivery. Nat. Commun. 15, 10804 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Hanna, A. R., Issadore, D. A. & Mitchell, M. J. High-throughput platforms for machine learning-guided lipid nanoparticle design. Nat. Rev. Mater. 11, 50–64 (2026).

    Article  Google Scholar 

  163. Xu, P., Ji, X., Li, M. & Lu, W. Small data machine learning in materials science. npj Comput. Mater. 9, 42 (2023).

    Article  Google Scholar 

  164. Fromer, J. C. & Coley, C. W. An algorithmic framework for synthetic cost-aware decision making in molecular design. Nat. Comput. Sci. 4, 440–450 (2024).

    Article  PubMed  Google Scholar 

  165. US Food and Drug Administration. Integrating Randomized Controlled Trials for Drug and Biological Products into Routine Clinical Practice. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/integrating-randomized-controlled-trials-drug-and-biological-products-routine-clinical-practice (2024).

  166. Di, J. et al. Biodistribution and non-linear gene expression of mRNA LNPs affected by delivery route and particle size. Pharm. Res. 39, 105–114 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Murciano-Goroff, Y. R., Warner, A. B. & Wolchok, J. D. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res. 30, 507–519 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Zhang, Z., Liu, X., Chen, D. & Yu, J. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct. Target. Ther. 7, 258 (2022).

    PubMed  PubMed Central  Google Scholar 

  169. Bruni, D., Angell, H. K. & Galon, J. The immune contexture and Immunoscore in cancer prognosis and therapeutic efficacy. Nat. Rev. Cancer 20, 662–680 (2020).

    Article  CAS  PubMed  Google Scholar 

  170. Zhu, Y. et al. An mRNA lipid nanoparticle-incorporated nanofiber–hydrogel composite for cancer immunotherapy. Nat. Commun. 16, 5707 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Chen, Y. et al. A radiotherapy-responsive peptide hydrogel for pulsatile release of mRNA-LNPs synergizes with immune activation to prevent breast cancer recurrence. Adv. Mater. 38, e17770 (2026).

    CAS  PubMed  Google Scholar 

来源:Nature Biotechnology · nature.com

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