Wolchok, J. D. et al. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 392, 11–22 (2025).
Irvine, D. J., Maus, M. V., Mooney, D. J. & Wong, W. W. The future of engineered immune cell therapies. Science 378, 853–858 (2022).
Sharma, P. et al. Immune checkpoint therapy—current perspectives and future directions. Cell 186, 1652–1669 (2023).
Gaynor, N., Crown, J. & Collins, D. M. Immune checkpoint inhibitors: key trials and an emerging role in breast cancer. Semin. Cancer Biol. 79, 44–57 (2022).
Patel, S. A. & Minn, A. J. Combination cancer therapy with immune checkpoint blockade: mechanisms and strategies. Immunity 48, 417–433 (2018).
Sellars, M. C., Wu, C. J. & Fritsch, E. F. Cancer vaccines: building a bridge over troubled waters. Cell 185, 2770–2788 (2022).
Zappasodi, R., Merghoub, T. & Wolchok, J. D. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell 33, 581–598 (2018).
Ninmer, E. K., Xu, F. & Slingluff, C. L. Jr The landmark series: cancer vaccines for solid tumors. Ann. Surg. Oncol. 32, 1443–1452 (2025).
Lin, M. J. et al. Cancer vaccines: the next immunotherapy frontier. Nat. Cancer 3, 911–926 (2022).
Katsikis, P. D., Ishii, K. J. & Schliehe, C. Challenges in developing personalized neoantigen cancer vaccines. Nat. Rev. Immunol. 24, 213–227 (2024).
Graciotti, M. & Kandalaft, L. E. Vaccines for cancer prevention: exploring opportunities and navigating challenges. Nat. Rev. Drug Discov. (2024).
Gilboa, E. The makings of a tumor rejection antigen. Immunity 11, 263–270 (1999).
Clark, K. T. & Trimble, C. L. Current status of therapeutic HPV vaccines. Gynecol. Oncol. 156, 503–510 (2020).
De Plaen, E. et al. Immunogenic (tum−) variants of mouse tumor P815: cloning of the gene of tum− antigen P91A and identification of the tum− mutation. Proc. Natl Acad. Sci. USA 85, 2274–2278 (1988).
Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).
Kvistborg, P. et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+ T cell response. Sci. Transl. Med. 6, 254ra128 (2014).
Subudhi, S. K. et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci. Transl. Med. 12, eaaz3577 (2020).
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Aggarwal, C. et al. Assessment of tumor mutational burden and outcomes in patients with diverse advanced cancers treated with immunotherapy. JAMA Netw. Open 6, e2311181 (2023).
Turajlic, S. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).
Chen, X. et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 13, 974 (2022).
Karakas, B., Bachman, K. E. & Park, B. H. Mutation of the PIK3CA oncogene in human cancers. Br. J. Cancer 94, 455–459 (2006).
Hofmann, M. H., Gerlach, D., Misale, S., Petronczki, M. & Kraut, N. Expanding the reach of precision oncology by drugging all KRAS mutants. Cancer Discov. 12, 924–937 (2022).
Bonaventura, P. et al. Identification of shared tumor epitopes from endogenous retroviruses inducing high-avidity cytotoxic T cells for cancer immunotherapy. Sci. Adv. 8, eabj3671 (2022).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
Johanns, T. M. et al. Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. Oncoimmunology 8, e1561106 (2019).
Braun, D. A. et al. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature 639, 474–482 (2025). This phase I clinical trial evaluated personalized peptide vaccines targeting neoantigens in patients with renal cell carcinoma following successful surgical resection, with no relapse detected in nine out of nine vaccinated patients after 40 months of follow-up.
Saxena, M. et al. Atezolizumab plus personalized neoantigen vaccination in urothelial cancer: a phase 1 trial. Nat. Cancer 6, 988–999 (2025).
Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).
Everson, R. G. et al. TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II trial. Nat. Commun. 15, 3882 (2024).
Fan, T. et al. Therapeutic cancer vaccines: advancements, challenges and prospects. Signal Transduct. Target. Ther. 8, 450 (2023).
Rappaport, A. R. et al. A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 30, 1013–1022 (2024).
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).
D’Alise, A. M. et al. Phase I trial of viral vector-based personalized vaccination elicits robust neoantigen-specific antitumor T-cell responses. Clin. Cancer Res. 30, 2412–2423 (2024).
Yarchoan, M. et al. Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial. Nat. Med. 30, 1044–1053 (2024).
Zhang, X. et al. Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients. Genome Med. 16, 131 (2024).
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).
O’Shea, A. E. et al. Phase II trial of nelipepimut-S peptide vaccine in women with ductal carcinoma in situ. Cancer Prev. Res. (Phila.) 16, 331–341 (2023).
Mittendorf, E. A. et al. Efficacy and safety analysis of nelipepimut-S vaccine to prevent breast cancer recurrence: a randomized, multicenter, phase III clinical trial. Clin. Cancer Res. 25, 4248–4254 (2019).
Montauti, E., Oh, D. Y. & Fong, L. CD4+ T cells in antitumor immunity. Trends Cancer 10, 969–985 (2024).
Bijker, M. S. et al. Superior induction of anti-tumor CTL immunity by extended peptide vaccines involves prolonged, DC-focused antigen presentation. Eur. J. Immunol. 38, 1033–1042 (2008).
Rosalia, R. A. et al. Dendritic cells process synthetic long peptides better than whole protein, improving antigen presentation and T‐cell activation. Eur. J. Immunol. 43, 2554–2565 (2013).
Kuna, M., Mahdi, F., Chade, A. R. & Bidwell, G. L. Molecular size modulates pharmacokinetics, biodistribution, and renal deposition of the drug delivery biopolymer elastin-like polypeptide. Sci. Rep. 8, 7923 (2018).
Trevaskis, N. L., Kaminskas, L. M. & Porter, C. J. H. From sewer to saviour — targeting the lymphatic system to promote drug exposure and activity. Nat. Rev. Drug Discov. 14, 781–803 (2015).
Moynihan, K. D. et al. Enhancement of peptide vaccine immunogenicity by increasing lymphatic drainage and boosting serum stability. Cancer Immunol. Res. 6, 1025–1038 (2018).
Böttger, R., Hoffmann, R. & Knappe, D. Differential stability of therapeutic peptides with different proteolytic cleavage sites in blood, plasma and serum. PLoS ONE 12, e0178943 (2017).
Yu, X. et al. Melittin-lipid nanoparticles target to lymph nodes and elicit a systemic anti-tumor immune response. Nat. Commun. 11, 1110 (2020).
Najafabadi, A. H. et al. Vaccine nanodiscs plus polyICLC elicit robust CD8+ T cell responses in mice and non-human primates. J. Control. Release 337, 168–178 (2021).
Lynn, G. M. et al. Peptide–TLR-7/8a conjugate vaccines chemically programmed for nanoparticle self-assembly enhance CD8 T-cell immunity to tumor antigens. Nat. Biotechnol. 38, 320–332 (2020).
Lynn, G. M. et al. In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. Nat. Biotechnol. 33, 1201–1210 (2015).
Reddy, S. T. et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat. Biotechnol. 25, 1159–1164 (2007).
Teplensky, M. H. et al. Multi-antigen spherical nucleic acid cancer vaccines. Nat. Biomed. Eng. 7, 911–927 (2023).
Bachmann, M. F. & Jennings, G. T. Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat. Rev. Immunol. 10, 787–796 (2010).
Baharom, F. et al. Intravenous nanoparticle vaccination generates stem-like TCF1+ neoantigen-specific CD8+ T cells. Nat. Immunol. 22, 41–52 (2021).
Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat. Mater. 16, 489–496 (2016). This study reported the development of synthetic lipid nanodiscs carrying neoantigen peptides and adjuvant molecules that showed efficient targeting to lymph nodes, leading to strong antitumour immunity in preclinical mouse models of cancer.
Irvine, D. J., Aung, A. & Silva, M. Controlling timing and location in vaccines. Adv. Drug Deliv. Rev. 158, 91–115 (2020).
Baharom, F. et al. Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment. Cell 185, 4317–4332.e15 (2022). This study demonstrated that nanoparticles carrying peptide antigens and molecular adjuvants administered intravenously can simultaneously target dendritic cells in lymphoid organs and directly accumulate in tumour tissues, triggering simultaneous priming of new T cell responses and remodelling the tumour microenvironment to promote antitumour immunity.
Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014). This study demonstrated the concept of ‘albumin hitchhiking’ for the targeting of peptide antigens and molecular adjuvants to lymph nodes, showing this to be a very potent strategy for amplifying vaccine responses in preclinical mouse models of cancer.
Ma, L. et al. Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019).
Rakhra, K. et al. Exploiting albumin as a mucosal vaccine chaperone for robust generation of lung-resident memory T cells. Sci. Immunol. 6, eabd8003 (2021).
Wang, C. et al. Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade. Cell Rep. 37, 110021 (2021).
Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016).
Pant, S. et al. Lymph-node-targeted, mKRAS-specific amphiphile vaccine in pancreatic and colorectal cancer: the phase 1 AMPLIFY-201 trial. Nat. Med. 30, 531–542 (2024). This phase I study reported promising immunogenicity, relapse-free survival and overall survival for pancreatic cancer patients who were positive for circulating tumour biomarkers following surgical resection and received a lymph node-targeted peptide vaccine targeting mutant KRAS antigen.
Devoe, C. E. et al. AMPLIFY-7P, a first-in-human safety and efficacy trial of adjuvant mKRAS-specific lymph node targeted amphiphile ELI-002 7P vaccine in patients with minimal residual disease–positive pancreatic and colorectal cancer. J. Clin. Oncol. 42, 2636–2636 (2024).
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. (2025).
McNeil, L.K. et al. 1473 AMPLIFY-7P phase 1a: lymph node-targeted amphiphile therapeutic cancer vaccine in patients with high relapse risk KRAS mutated pancreatic ductal adenocarcinoma and colorectal cancer. J. Immunother. Cancer (2024).
Elicio Therapeutics. A study of ELI-002 7P in subjects with KRAS/NRAS mutated solid tumors (AMPLIFY-7P). ClinicalTrials.gov (2025).
Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–401 (2016). This study demonstrated that mRNA carried in near-neutral-charge LPXs administered intravenously can effectively target, transfect and activate dendritic cells systemically, providing strong vaccine priming in preclinical mouse models, and reported early phase I vaccination data in cancer patients.
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
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).
Hou, X., Zaks, T., Langer, R. & Dong, Y. Lipid nanoparticles for mRNA delivery. Nat. Rev. Mater. 6, 1078–1094 (2021).
Akinc, A. et al. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs. Nat. Nanotechnol. 14, 1084–1087 (2019).
Lee, J. M. et al. The phase 3 INTerpath-002 study design: individualized neoantigen therapy (INT) V940 (mRNA-4157) plus pembrolizumab vs placebo plus pembrolizumab for resected early-stage non-small-cell lung cancer (NSCLC). J. Clin. Oncol. 42, TPS8116 (2024).
Alameh, M.-G. et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity 54, 2877–2892.e7 (2021). This study was one of the first to demonstrate that LNP formulations used for mRNA delivery have intrinsic adjuvant activity that promotes immunity to co-administered antigens.
Verbeke, R., Hogan, M. J., Loré, K. & Pardi, N. Innate immune mechanisms of mRNA vaccines. Immunity 55, 1993–2005 (2022).
Semple, S. C. et al. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 28, 172–176 (2010).
Kowalski, P. S., Rudra, A., Miao, L. & Anderson, D. G. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710–728 (2019).
Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017).
Carvalho, T. Personalized anti-cancer vaccine combining mRNA and immunotherapy tested in melanoma trial. Nat. Med. 29, 2379–2380 (2023).
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). This randomized phase II clinical trial reported a substantially reduced risk of death due to recurrence in melanoma patients who received a personalized mRNA neoantigen-targeting vaccine in combination with checkpoint blockade versus checkpoint blockade alone.
Ladwa, R. et al. 940TiP INTerpath-007: a phase II/III, adaptive, randomized study of neoadjuvant and adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) for treatment of resectable locally advanced (LA) cutaneous squamous cell carcinoma (cSCC). Ann. Oncol. 35, S652–S653 (2024).
Motzer, R. J. et al. INTerpath-004: a phase 2, randomized, double-blind study of adjuvant pembrolizumab (pembro) with V940 (mRNA-4157) or placebo for renal cell carcinoma (RCC). J. Clin. Oncol. 43, TPS610 (2025).
Sonpavde, G. P. et al. Phase 1/2 INTerpath-005 study: V940 (mRNA-4157) plus pembrolizumab with or without enfortumab vedotin (EV) for resected high-risk muscle-invasive urothelial carcinoma (MIUC). J. Clin. Oncol. 43, TPS893 (2025).
Lindsay, K. E. et al. Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging. Nat. Biomed. Eng. 3, 371–380 (2019).
Liang, F. et al. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol. Ther. 25, 2635–2647 (2017).
Buckley, M. et al. Visualizing lipid nanoparticle trafficking for mRNA vaccine delivery in non-human primates. Mol. Ther. 33, 1105–1117 (2025).
Blizard, G. S. et al. Monitoring mRNA vaccine antigen expression in vivo using PET/CT. Nat. Commun. 16, 2234 (2025).
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, 2209–2223 (2024).
Low, J. G. et al. A phase I/II randomized, double-blinded, placebo-controlled trial of a self-amplifying Covid-19 mRNA vaccine. npj Vaccines 7, 161 (2022).
Saraf, A. et al. An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial. Nat. Med. 30, 1363–1372 (2024).
Zhang, Y. et al. Small circular RNAs as vaccines for cancer immunotherapy. Nat. Biomed. Eng. 9, 249–267 (2025).
Gong, Z. et al. Recent advances and perspectives on the development of circular RNA cancer vaccines. npj Vaccines 10, 41 (2025).
First self-amplifying mRNA vaccine approved. Nat. Biotechnol. 42, 4 (2024).
Yu, J. et al. Targeted LNPs deliver IL-15 superagonists mRNA for precision cancer therapy. Biomaterials 317, 123047 (2025).
Zhang, D. et al. Enhancing CRISPR/Cas gene editing through modulating cellular mechanical properties for cancer therapy. Nat. Nanotechnol. 17, 777–787 (2022).
Hu, X. et al. The hybrid lipoplex induces cytoskeletal rearrangement via autophagy/RhoA signaling pathway for enhanced anticancer gene therapy. Nat. Commun. 16, 339 (2025).
Grunwitz, C. et al. HPV16 RNA-LPX vaccine mediates complete regression of aggressively growing HPV-positive mouse tumors and establishes protective T cell memory. Oncoimmunology 8, e1629259 (2019).
Salomon, N. et al. Local radiotherapy and E7 RNA-LPX vaccination show enhanced therapeutic efficacy in preclinical models of HPV16+ cancer. Cancer Immunol. Immunother. 71, 1975–1988 (2022).
Lopez, J. et al. Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial. Nat. Med. 31, 152–164 (2025).
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). This paper reported results from a small phase I clinical trial showing that mRNA vaccines targeting personalized neoantigens were immunogenic and elicited encouraging recurrence-free and overall survival in pancreatic cancer patients at high risk for relapse following surgery.
Sethna, Z. et al. RNA neoantigen vaccines prime long-lived CD8+ T cells in pancreatic cancer. Nature 639, 1042–1051 (2025).
Mendez-Gomez, H. R. et al. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell 187, 2521–2535.e21 (2024).
Haabeth, O. A. W. et al. mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice. Proc. Natl Acad. Sci. USA 115, E9153–E9161 (2018).
Ben-Akiva, E., Chapman, A., Mao, T. & Irvine, D. J. Linking vaccine adjuvant mechanisms of action to function. Sci. Immunol. 10, eado5937 (2025).
Pulendran, B., Arunachalam, P. S. & O’Hagan, D. T. Emerging concepts in the science of vaccine adjuvants. Nat. Rev. Drug Discov. (2021).
Zimmermann, J. et al. A novel prophylaxis strategy using liposomal vaccine adjuvant CAF09b protects against influenza virus disease. Int. J. Mol. Sci. 23, 1850 (2022).
Mørk, S. K. et al. First in man study: Bcl-Xl_42-CAF®09b vaccines in patients with locally advanced prostate cancer. Front. Immunol. 14, 1122977 (2023).
Mørk, S. K. et al. Dose escalation study of a personalized peptide-based neoantigen vaccine (EVX-01) in patients with metastatic melanoma. J. Immunother. Cancer 12, e008817 (2024).
Banga, R. J., Chernyak, N., Narayan, S. P., Nguyen, S. T. & Mirkin, C. A. Liposomal spherical nucleic acids. J. Am. Chem. Soc. 136, 9866–9869 (2014).
Ferrer, J. R. et al. Structure-dependent biodistribution of liposomal spherical nucleic acids. ACS Nano 14, 1682–1693 (2020).
Meckes, B., Banga, R. J., Nguyen, S. T. & Mirkin, C. A. Enhancing the stability and immunomodulatory activity of liposomal spherical nucleic acids through lipid‐tail DNA modifications. Small 14, 1702909 (2018).
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).
Seenappa, L. M. et al. Amphiphile-CpG vaccination induces potent lymph node activation and COVID-19 immunity in mice and non-human primates. npj Vaccines 7, 128 (2022).
Martin, J. T. et al. Combined PET and whole-tissue imaging of lymphatic-targeting vaccines in non-human primates. Biomaterials 275, 120868 (2021).
Speetjens, F. M. et al. Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions. J. Immunother. Cancer 10, e005016 (2022).
Zhivaki, D. et al. Inflammasomes within hyperactive murine dendritic cells stimulate long-lived T cell-mediated anti-tumor immunity. Cell Rep. 33, 108381 (2020).
Zanoni, I., Tan, Y., Di Gioia, M., Springstead, J. R. & Kagan, J. C. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity 47, 697–709.e3 (2017).
Silva, M. et al. A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity. Sci. Immunol. 6, eabf1152 (2021).
Bengtsson, K. L., Morein, B. & Osterhaus, A. D. ISCOM technology-based Matrix M™ adjuvant: success in future vaccines relies on formulation. Expert Rev. Vaccines 10, 401–403 (2011).
Mochida, Y. & Uchida, S. mRNA vaccine designs for optimal adjuvanticity and delivery. RNA Biol. 21, 422–448 (2024).
Yang, K. et al. Biodegradable lipid-modified poly(guanidine thioctic acid)s: a fortifier of lipid nanoparticles to promote the efficacy and safety of mRNA cancer vaccines. J. Am. Chem. Soc. 146, 11679–11693 (2024).
Omo-Lamai, S. et al. Limiting endosomal damage sensing reduces inflammation triggered by lipid nanoparticle endosomal escape. Nat. Nanotechnol. 20, 1285–1297 (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).
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).
Han, X. et al. Adjuvant lipidoid-substituted lipid nanoparticles augment the immunogenicity of SARS-CoV-2 mRNA vaccines. Nat. Nanotechnol. (2023).
Zhang, Y. et al. STING agonist-derived LNP-mRNA vaccine enhances protective immunity against SARS-CoV-2. Nano Lett. 23, 2593–2600 (2023).
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).
Chen, W., Yan, W. & Huang, L. A simple but effective cancer vaccine consisting of an antigen and a cationic lipid. Cancer Immunol. Immunother. 57, 517–530 (2008).
Gandhapudi, S. K. et al. Antigen priming with enantiospecific cationic lipid nanoparticles induces potent antitumor CTL responses through novel induction of a type I IFN response. J. Immunol. 202, 3524–3536 (2019).
Rumfield, C. S., Pellom, S. T., Morillon, Y. M. II, Schlom, J. & Jochems, C. Immunomodulation to enhance the efficacy of an HPV therapeutic vaccine. J. Immunother. Cancer 8, e000612 (2020).
Kahles, A. et al. Comprehensive analysis of alternative splicing across tumors from 8,705 patients. Cancer Cell 34, 211–224.e6 (2018).
Reynisson, B., Alvarez, B., Paul, S., Peters, B. & Nielsen, M. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 48, W449–W454 (2020).
Li, G., Iyer, B., Prasath, V. B. S., Ni, Y. & Salomonis, N. DeepImmuno: deep learning-empowered prediction and generation of immunogenic peptides for T-cell immunity. Brief. Bioinform. 22, bbab160 (2021).
Schmidt, J. et al. Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting. Cell Rep. Med. 2, 100194 (2021).
Wu, J. et al. DeepHLApan: a deep learning approach for neoantigen prediction considering both HLA-peptide binding and immunogenicity. Front. Immunol. 10, 2559 (2019).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Martin, S. D. et al. Low mutation burden in ovarian cancer may limit the utility of neoantigen-targeted vaccines. PloS ONE 11, e0155189 (2016).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Chen, H. et al. Chemical and topological design of multicapped mRNA and capped circular RNA to augment translation. Nat. Biotechnol. (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).
Feng, Z. et al. An in vitro-transcribed circular RNA targets the mitochondrial inner membrane cardiolipin to ablate EIF4G2+/PTBP1+ pan-adenocarcinoma. Nat. Cancer 5, 30–46 (2024).
Morse, M. A. et al. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Ther. 30, 803–811 (2023).
Aliahmad, P., Miyake-Stoner, S. J., Geall, A. J. & Wang, N. S. Next generation self-replicating RNA vectors for vaccines and immunotherapies. Cancer Gene Ther. 30, 785–793 (2023).
Kim, D. Y. et al. Enhancement of protein expression by alphavirus replicons by designing self-replicating subgenomic RNAs. Proc. Natl Acad. Sci. USA 111, 10708–10713 (2014).
Oda, Y. et al. 12-month persistence of immune responses to self-amplifying mRNA COVID-19 vaccines: ARCT-154 versus BNT162b2 vaccine. Lancet Infect. Dis. (2024).
