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
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。
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).
Shi, Y. et al. Chemically modified platforms for better RNA therapeutics. Chem. Rev. 124, 929–1033 (2024).
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).
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).
Yaremenko, A. V., Khan, M. M., Zhen, X., Tang, Y. & Tao, W. Clinical advances of mRNA vaccines for cancer immunotherapy. Med 6, 100562 (2025).
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).
Lopez, J. et al. Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial. Nat. Med. 31, 152–164 (2025).
Sahin, U. et al. Individualized mRNA vaccines evoke durable T cell immunity in adjuvant TNBC. Nature 651, 1088–1096 (2026).
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).
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).
Peng, K., Zhao, X., Fu, Y.-X. & Liang, Y. Eliciting antitumor immunity via therapeutic cancer vaccines. Cell. Mol. Immunol. 22, 840–868 (2025).
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).
Hunter, T. L. et al. In vivo CAR T cell generation to treat cancer and autoimmune disease. Science 388, 1311–1317 (2025).
Wang, Q. et al. In vivo CD19 CAR T-cell therapy for refractory systemic lupus erythematosus. N. Engl. J. Med. 393, 1542–1544 (2025).
Bot, A. et al. In vivo chimeric antigen receptor (CAR)-T cell therapy. Nat. Rev. Drug Discov. 25, 116–137 (2026).
Martini, D. J. & Wu, C. J. The future of personalized cancer vaccines. Cancer Discov. 15, 1315–1324 (2025).
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).
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).
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).
Park, C. G. et al. Extended release of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. Sci. Transl. Med. 10, eaar1916 (2018).
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).
Bezu, L. et al. Perioperative immunosuppressive factors during cancer surgery: an updated review. Cancers 16, 2304 (2024).
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).
Cheng, X., Zhang, H., Hamad, A., Huang, H. & Tsung, A. in Seminars in Cancer Biology 408–419 (Elsevier).
Chen, S. et al. Nanotechnology-based mRNA vaccines. Nat. Rev. Methods Primers 3, 63 (2023).
Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
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).
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).
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).
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).
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).
Anderson, B. R. et al. Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation. Nucleic acids Res. 38, 5884–5892 (2010).
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).
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).
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).
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).
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).
West, J. D. et al. The quantitative impact of 3′ UTRs on gene expression. Nucleic Acids Res. 53, gkaf568 (2025).
Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2023).
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).
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).
Morse, M. A. et al. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Ther. 30, 803–811 (2023).
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).
Miao, L. et al. Synergistic lipid compositions for albumin receptor mediated delivery of mRNA to the liver. Nat. Commun. 11, 2424 (2020).
Ngo, W. et al. Identifying cell receptors for the nanoparticle protein corona using genome screens. Nat. Chem. Biol. 18, 1023–1031 (2022).
Voke, E. et al. Protein corona formed on lipid nanoparticles compromises delivery efficiency of mRNA cargo. Nat. Commun. 16, 8699 (2025).
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).
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).
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).
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).
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).
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).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016).
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).
Ndeupen, S. et al. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. iScience 24, 103479 (2021).
Luo, Z. et al. Spleen-targeted mRNA vaccine doped with manganese adjuvant for robust anticancer immunity in vivo. ACS Nano 18, 30701–30715 (2024).
Budczies, J. et al. Tumour mutational burden: clinical utility, challenges and emerging improvements. Nat. Rev. Clin. Oncol. 21, 725–742 (2024).
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Katsikis, P. D., Ishii, K. J. & Schliehe, C. Challenges in developing personalized neoantigen cancer vaccines. Nat. Rev. Immunol. 24, 213–227 (2024).
Sade-Feldman, M. et al. Resistance to checkpoint blockade therapy through inactivation of antigen presentation. Nat. Commun. 8, 1136 (2017).
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).
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).
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).
De Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).
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).
Escobar, G., Berger, T. R. & Maus, M. V. CAR-T cells in solid tumors: challenges and breakthroughs. Cell Rep. Med. 6, 102353 (2025).
Fan, T. et al. Therapeutic cancer vaccines: advancements, challenges and prospects. Signal Transduct. Target. Ther. 8, 450 (2023).
Grippin, A. J. et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature 647, 488–497 (2025).
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).
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).
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).
Bain, C., Myles, P., Corcoran, T. & Dieleman, J. M. Postoperative systemic inflammatory dysregulation and corticosteroids: a narrative review. Anaesthesia 78, 356–370 (2023).
Allen, J. E. IL-4 and IL-13: regulators and effectors of wound repair. Annu. Rev. Immunol. 41, 229–254 (2023).
Topalian, S. L., Taube, J. M. & Pardoll, D. M. Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367, eaax0182 (2020).
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).
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).
Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023).
Forde, P. M. et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N. Engl. J. Med. 386, 1973–1985 (2022).
Forde, P. M. et al. Overall survival with neoadjuvant nivolumab plus chemotherapy in lung cancer. N. Engl. J. Med. 393, 741–752 (2025).
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).
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).
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).
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).
Hatit, M. Z. et al. Species-dependent in vivo mRNA delivery and cellular responses to nanoparticles. Nat. Nanotechnol. 17, 310–318 (2022).
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).
Hassett, K. J. et al. mRNA vaccine trafficking and resulting protein expression after intramuscular administration. Mol. Ther. Nucleic Acids 35, 102083 (2024).
Buckley, M. et al. Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates. Mol. Ther. 33, 1105–1117 (2025).
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).
Dowell, W. et al. Distinct inflammatory programs underlie the intramuscular lipid nanoparticle response. ACS Nano 18, 33058–33072 (2024).
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).
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).
Zhang, T. et al. Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo. iScience 27, 109804 (2024).
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).
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).
Hassett, K. J. et al. Impact of lipid nanoparticle size on mRNA vaccine immunogenicity. J. Controlled Rel. 335, 237–246 (2021).
Okuda, K. et al. On the size-regulation of RNA-loaded lipid nanoparticles synthesized by microfluidic device. J. Controlled Rel. 348, 648–659 (2022).
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).
Kawaguchi, Y. et al. Modulating immunogenicity and reactogenicity in mRNA-lipid nanoparticle vaccines through lipid component optimization. ACS Nano 19, 27977–28001 (2025).
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).
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).
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).
van Straten, D. et al. Biofluid specific protein coronas affect lipid nanoparticle behavior in vitro. J. Controlled Rel. 373, 481–492 (2024).
Sharma, P., Hoorn, D., Aitha, A., Breier, D. & Peer, D. The immunostimulatory nature of mRNA lipid nanoparticles. Adv. Drug Deliv. Rev. 205, 115175 (2024).
Zhao, S. et al. Acid-degradable lipid nanoparticles enhance the delivery of mRNA. Nat. Nanotechnol. 19, 1702–1711 (2024).
Maier, M. A. et al. Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol. Ther. 21, 1570–1578 (2013).
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).
Jörgensen, A. M., Wibel, R. & Bernkop-Schnürch, A. Biodegradable cationic and ionizable cationic lipids: a roadmap for safer pharmaceutical excipients. Small 19, 2206968 (2023).
Gilleron, J. et al. Image-based analysis of lipid nanoparticle-mediated siRNA delivery, intracellular trafficking and endosomal escape. Nat. Biotechnol. 31, 638–646 (2013).
Paramasivam, P. et al. Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscale. J. Cell Biol. 221, e202110137 (2021).
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).
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).
Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).
Arunachalam, P. S. et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature 596, 410–416 (2021).
Yamaguchi, Y. et al. Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells. JCI Insight 7, e163347 (2022).
Li, S., Zou, Y., McMasters, A., Chen, F. & Yan, J. Trained immunity: a new player in cancer immunotherapy. eLife 14, e104920 (2025).
Sui, Y. & Berzofsky, J. A. Trained immunity inducers in cancer immunotherapy. Front. Immunol. 15, 1427443 (2024).
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).
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).
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).
Wiener, A. A. et al. Reexamining time from breast cancer diagnosis to primary breast surgery. JAMA Surg. 158, 485–492 (2023).
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).
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).
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).
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).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Maier, B. et al. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature 580, 257–262 (2020).
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).
DeNardo, D. G. & Ruffell, B. Macrophages as regulators of tumour immunity and immunotherapy. Nat. Rev. Immunol. 19, 369–382 (2019).
Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).
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).
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).
Zhang, M. et al. STING-activating polymers boost lymphatic delivery of mRNA vaccine to potentiate cancer immunotherapy. Adv. Mater. 37, 2412654 (2025).
Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. 18, 1105–1114 (2023).
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).
Xie, N. et al. Neoantigens: promising targets for cancer therapy. Signal Transduct. Target. Ther. 8, 9 (2023).
Monroe, J. et al. N1-methylpseudouridine and pseudouridine modifications modulate mRNA decoding during translation. Nat. Commun. 15, 8119 (2024).
Chen, H. et al. Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation. Nat. Biotechnol. 43, 1128–1143 (2025).
Castillo-Hair, S. et al. Optimizing 5’UTRs for mRNA-delivered gene editing using deep learning. Nat. Commun. 15, 5284 (2024).
Zhang, H. et al. Deep generative models design mRNA sequences with enhanced translational capacity and stability. Science 390, eadr8470 (2025).
Li, Y. et al. Deep generative optimization of mRNA codon sequences for enhanced mRNA translation and therapeutic efficacy. Nat. Commun. 16, 9957 (2025).
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).
Du, Y. et al. Efficient circular RNA synthesis for potent rolling circle translation. Nat. Biomed. Eng. 9, 1062–1074 (2025).
Fukuchi, K. et al. Internal cap-initiated translation for efficient protein production from circular mRNA. Nat. Biotechnol. 44, 120–132 (2025).
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).
Guo, C. et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature 620, 200–208 (2023).
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).
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).
Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. npj Vaccines 4, 7 (2019).
Yadav, M. et al. Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing. Nature 515, 572–576 (2014).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Fan, T. et al. Lipopolyplex-formulated mRNA cancer vaccine elicits strong neoantigen-specific T cell responses and antitumor activity. Sci. Adv. 10, eadn9961 (2024).
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).
Yi, M. et al. Targeting cytokine and chemokine signaling pathways for cancer therapy. Signal Transduct. Target. Ther. 9, 176 (2024).
Del Prete, A. et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell. Mol. Immunol. 20, 432–447 (2023).
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).
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).
Li, B. et al. Accelerating ionizable lipid discovery for mRNA delivery using machine learning and combinatorial chemistry. Nat. Mater. 23, 1002–1008 (2024).
Xu, Y. et al. AGILE platform: a deep learning powered approach to accelerate LNP development for mRNA delivery. Nat. Commun. 15, 6305 (2024).
Witten, J. et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat. Biotechnol. 43, 1790–1799 (2025).
Wang, W. et al. Artificial intelligence-driven rational design of ionizable lipids for mRNA delivery. Nat. Commun. 15, 10804 (2024).
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).
Xu, P., Ji, X., Li, M. & Lu, W. Small data machine learning in materials science. npj Comput. Mater. 9, 42 (2023).
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).
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).
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).
Murciano-Goroff, Y. R., Warner, A. B. & Wolchok, J. D. The future of cancer immunotherapy: microenvironment-targeting combinations. Cell Res. 30, 507–519 (2020).
Zhang, Z., Liu, X., Chen, D. & Yu, J. Radiotherapy combined with immunotherapy: the dawn of cancer treatment. Signal Transduct. Target. Ther. 7, 258 (2022).
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).
Zhu, Y. et al. An mRNA lipid nanoparticle-incorporated nanofiber–hydrogel composite for cancer immunotherapy. Nat. Commun. 16, 5707 (2025).
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).
来源:Nature Biotechnology · nature.com