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mRNA-based cancer therapeutics

Nature Reviews Cancer volume 23, pages 526–543 (2023)Cite this article

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Abstract

Due to the fact that mRNA technology allows the production of diverse vaccines and treatments in a shorter time frame and with reduced expense compared to conventional approaches, there has been a surge in the use of mRNA-based therapeutics in recent years. With the aim of encoding tumour antigens for cancer vaccines, cytokines for immunotherapy, tumour suppressors to inhibit tumour development, chimeric antigen receptors for engineered T cell therapy or genome-editing proteins for gene therapy, many of these therapeutics have shown promising efficacy in preclinical studies, and some have even entered clinical trials. Given the evidence supporting the effectiveness and safety of clinically approved mRNA vaccines, coupled with growing interest in mRNA-based therapeutics, mRNA technology is poised to become one of the major pillars in cancer drug development. In this Review, we present in vitro transcribed mRNA-based therapeutics for cancer treatment, including the characteristics of the various types of synthetic mRNA, the packaging systems for efficient mRNA delivery, preclinical and clinical studies, current challenges and future prospects in the field. We anticipate the translation of promising mRNA-based treatments into clinical applications, to ultimately benefit patients.

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Fig. 1: In vitro transcribed mRNA for cancer therapeutics.
Fig. 2: The development of mRNA cancer vaccine encoding tumour-associated antigens or neoantigens.
Fig. 3: mRNA encoding cytokines and tumour suppressors for cancer therapy.
Fig. 4: mRNA encoding Cas9 mediated genome editing for cancer immunotherapy.
Fig. 5: In vitro and in vivo delivery of mRNA encoding CAR and TCR for T cell engineering.

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References

  1. Langer, R. & Folkman, J. Polymers for the sustained release of proteins and other macromolecules. Nature 263, 797–800 (1976). This work presents the first report of nucleic acids (DNA isolated from mouse cells) that can be encapsulated and delivered by tiny particles.

    CAS  PubMed  Google Scholar 

  2. Dimitriadis, G. J. Translation of rabbit globin mRNA introduced by liposomes into mouse lymphocytes. Nature 274, 923–924 (1978).

    CAS  PubMed  Google Scholar 

  3. Ostro, M. J., Giacomoni, D., Lavelle, D., Paxton, W. & Dray, S. Evidence for translation of rabbit globin mRNA after liposome-mediated insertion into a human cell line. Nature 274, 921–923 (1978).

    CAS  PubMed  Google Scholar 

  4. Kulkarni, J. A. et al. The current landscape of nucleic acid therapeutics. Nat. Nanotechnol. 16, 630–643 (2021).

    CAS  PubMed  Google Scholar 

  5. Dolgin, E. The tangled history of mRNA vaccines. Nature 597, 318–324 (2021). This review presents the discovery of mRNA, the in vitro synthesis of mRNA to the in vivo application of mRNA, which gives the reader an overview of the field.

    CAS  PubMed  Google Scholar 

  6. Cobb, M. Who discovered messenger RNA? Curr. Biol. 25, R526–R532 (2015).

    CAS  PubMed  Google Scholar 

  7. Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02413645 (2017).

  9. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03076385 (2022).

  10. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03014089 (2019).

  11. Szebeni, J. et al. Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines. Nat. Nanotechnol. 17, 337–346 (2022).

    CAS  PubMed  Google Scholar 

  12. Kirtane, A. R. et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 16, 369–384 (2021).

    CAS  PubMed  Google Scholar 

  13. Shin, M. D. et al. COVID-19 vaccine development and a potential nanomaterial path forward. Nat. Nanotechnol. 15, 646–655 (2020).

    CAS  PubMed  Google Scholar 

  14. Huang, X. et al. Nanotechnology-based strategies against SARS-CoV-2 variants. Nat. Nanotechnol. 17, 1027–1037 (2022).

    CAS  PubMed  Google Scholar 

  15. Qu, P. et al. Durability of booster mRNA vaccine against SARS-CoV-2 BA.2.12.1, BA.4, and BA.5 subvariants. N. Engl. J. Med. 387, 1329–1331 (2022).

    PubMed  Google Scholar 

  16. Sahin, U., Kariko, K. & Tureci, O. mRNA-based therapeutics-developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014).

    CAS  PubMed  Google Scholar 

  17. Wolff, J. A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 (1990).

    CAS  PubMed  Google Scholar 

  18. Kariko, 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).

    CAS  PubMed  Google Scholar 

  19. Huang, X. et al. The landscape of mRNA nanomedicine. Nat. Med. 28, 2273–2287 (2022). This review provides the latest advances and innovations in mRNA nanomedicine, in the context of ongoing clinical translation and future directions to improve clinical efficacy.

    CAS  PubMed  Google Scholar 

  20. Xiong, Q., Lee, G. Y., Ding, J., Li, W. & Shi, J. Biomedical applications of mRNA nanomedicine. Nano Res. 11, 5281–5309 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Polack, F. P. et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N. Engl. J. Med. 383, 2603–2615 (2020).

    CAS  PubMed  Google Scholar 

  22. Xiao, Y. et al. Emerging mRNA technologies: delivery strategies and biomedical applications. Chem. Soc. Rev. 51, 3828–3845 (2022). This review provides a summary and discussion of the progress, chemical designs and principles of mRNA technologies.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang, Y., Sun, C., Wang, C., Jankovic, K. E. & Dong, Y. Lipids and lipid derivatives for RNA delivery. Chem. Rev. 121, 12181–12277 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kong, N. et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Sci. Transl Med. 11, eaaw1565 (2019). This work presents a redox-responsive nanoparticle platform for the effective delivery of TP53 mRNA, which can markedly improve the sensitivity of tumour cells to rapamycin (mTOR) inhibitors for potent combinatorial cancer treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Islam, M. A. et al. Restoration of tumour-growth suppression in vivo via systemic nanoparticle-mediated delivery of PTEN mRNA. Nat. Biomed. Eng. 2, 850–864 (2018). This work provides proof-of-principle evidence of the in vivo restoration of mRNA-based tumour suppression.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Sahin, U. & Tureci, O. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  29. 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 

  30. Wang, H. X. et al. CRISPR/Cas9-based genome editing for disease modeling and therapy: challenges and opportunities for nonviral delivery. Chem. Rev. 117, 9874–9906 (2017).

    CAS  PubMed  Google Scholar 

  31. Katti, A., Diaz, B. J., Caragine, C. M., Sanjana, N. E. & Dow, L. E. CRISPR in cancer biology and therapy. Nat. Rev. Cancer 22, 259–279 (2022).

    CAS  PubMed  Google Scholar 

  32. 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). This work presents the mRNA nanoparticles binding to T cells to reprogramme T cells in situ to express cancer-specific CARs or TCRs to cause tumour regression.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Rurik, J. G. et al. CAR T cells produced in vivo to treat cardiac injury. Science 375, 91–96 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 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).

    CAS  PubMed  Google Scholar 

  37. Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022).

    CAS  PubMed  Google Scholar 

  38. Chen, R. et al. Engineering circular RNA for enhanced protein production. Nat. Biotechnol. 41, 262–272 (2022).

    PubMed  PubMed Central  Google Scholar 

  39. Muramatsu, H. et al. Lyophilization provides long-term stability for a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine. Mol. Ther. 30, 1941–1951 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Dolgin, E. Startups set off new wave of mRNA therapeutics. Nat. Biotechnol. 39, 1029–1031 (2021).

    CAS  PubMed  Google Scholar 

  42. Abramson, A. et al. Oral mRNA delivery using capsule-mediated gastrointestinal tissue injections. Matter 5, 975–987 (2022).

    CAS  Google Scholar 

  43. Kong, N. et al. Intravesical delivery of KDM6A-mRNA via mucoadhesive nanoparticles inhibits the metastasis of bladder cancer. Proc. Natl Acad. Sci. USA 119, e2112696119 (2022). This work presents a mucoadhesive nanoparticle strategy to restore KDM6A expression in bladder cancer, which is helpful for mechanistic understanding and translational study of bladder-related diseases.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Tao, W. & Peppas, N. A. Robotic pills for gastrointestinal-tract-targeted oral mRNA delivery. Matter 5, 775–777 (2022). This work previews the design of robotic pills for gastrointestinal-tract-targeted oral mRNA delivery, which may open up a new avenue for the oral mRNA medicines.

    CAS  Google Scholar 

  45. Melton, D. A. et al. Efficient in vitro synthesis of biologically active RNA and RNA hybridization probes from plasmids containing a bacteriophage SP6 promoter. Nucleic Acids Res. 12, 7035–7056 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Schlaeger, T. M. et al. A comparison of non-integrating reprogramming methods. Nat. Biotechnol. 33, 58–63 (2015).

    CAS  PubMed  Google Scholar 

  47. Hajj, K. A. & Whitehead, K. A. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat. Rev. Mater. 2, 17056 (2017).

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim, Y. K. RNA therapy: rich history, various applications and unlimited future prospects. Exp. Mol. Med. 54, 455–465 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Jemielity, J., Kowalska, J., Rydzik, A. M. & Darzynkiewicz, E. Synthetic mRNA cap analogs with a modified triphosphate bridge – synthesis, applications and prospects. N. J. Chem. 34, 829–844 (2010).

    CAS  Google Scholar 

  51. Ziemniak, M., Strenkowska, M., Kowalska, J. & Jemielity, J. Potential therapeutic applications of RNA cap analogs. Future Med. Chem. 5, 1141–1172 (2013).

    CAS  PubMed  Google Scholar 

  52. Martinez-Salas, E., Francisco-Velilla, R., Fernandez-Chamorro, J. & Embarek, A. M. Insights into structural and mechanistic features of viral IRES elements. Front. Microbiol. 8, 2629 (2017).

    PubMed  Google Scholar 

  53. Zarghampoor, F., Azarpira, N., Khatami, S. R., Behzad-Behbahani, A. & Foroughmand, A. M. Improved translation efficiency of therapeutic mRNA. Gene 707, 231–238 (2019).

    CAS  PubMed  Google Scholar 

  54. Zhang, Z. et al. Genetic analyses support the contribution of mRNA N(6)-methyladenosine (m(6)A) modification to human disease heritability. Nat. Genet. 52, 939–949 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Alexaki, A. et al. Effects of codon optimization on coagulation factor IX translation and structure: implications for protein and gene therapies. Sci. Rep. 9, 15449 (2019).

    PubMed  PubMed Central  Google Scholar 

  56. Jemielity, J. et al. Novel “anti-reverse” cap analogs with superior translational properties. RNA 9, 1108–1122 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Rabinovich, P. M. et al. Synthetic messenger RNA as a tool for gene therapy. Hum. Gene Ther. 17, 1027–1035 (2006).

    CAS  PubMed  Google Scholar 

  58. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Linares-Fernandez, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2020).

    CAS  PubMed  Google Scholar 

  60. Kariko, K., Muramatsu, H., Ludwig, J. & Weissman, D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. 39, e142 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020).

    CAS  PubMed  Google Scholar 

  62. Igyarto, B. Z., Jacobsen, S. & Ndeupen, S. Future considerations for the mRNA-lipid nanoparticle vaccine platform. Curr. Opin. Virol. 48, 65–72 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  64. Lundstrom, K. Self-amplifying RNA viruses as RNA vaccines. Int. J. Mol. Sci. 21, 5130 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Bloom, K., van den Berg, F. & Arbuthnot, P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther. 28, 117–129 (2021).

    CAS  PubMed  Google Scholar 

  66. Balmayor, E. R. Synthetic mRNA - emerging new class of drug for tissue regeneration. Curr. Opin. Biotechnol. 74, 8–14 (2022).

    CAS  PubMed  Google Scholar 

  67. Beissert, T. et al. A trans-amplifying RNA vaccine strategy for induction of potent protective immunity. Mol. Ther. 28, 119–128 (2020).

    CAS  PubMed  Google Scholar 

  68. Fuller, D. H. & Berglund, P. Amplifying RNA vaccine development. N. Engl. J. Med. 382, 2469–2471 (2020).

    PubMed  Google Scholar 

  69. Chen, L. L. & Yang, L. Regulation of circRNA biogenesis. RNA Biol. 12, 381–388 (2015).

    PubMed  PubMed Central  Google Scholar 

  70. Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44, 1370–1383 (2016).

    CAS  PubMed  Google Scholar 

  71. Kwon, S., Kwon, M., Im, S., Lee, K. & Lee, H. mRNA vaccines: the most recent clinical applications of synthetic mRNA. Arch. Pharm. Res. 45, 245–262 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Morse, D. E. & Yanofsky, C. Polarity and the degradation of mRNA. Nature 224, 329–331 (1969).

    CAS  PubMed  Google Scholar 

  73. Wang, C. & Liu, H. Factors influencing degradation kinetics of mRNAs and half-lives of microRNAs, circRNAs, lncRNAs in blood in vitro using quantitative PCR. Sci. Rep. 12, 7259 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bessis, N., GarciaCozar, F. J. & Boissier, M. C. Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther. 11, S10–S17 (2004).

    CAS  PubMed  Google Scholar 

  75. Thomas, C. E., Ehrhardt, A. & Kay, M. A. Progress and problems with the use of viral vectors for gene therapy. Nat. Rev. Genet. 4, 346–358 (2003).

    CAS  PubMed  Google Scholar 

  76. Meng, C., Chen, Z., Li, G., Welte, T. & Shen, H. Nanoplatforms for mRNA therapeutics. Adv. Ther. 4, 2000099 (2020).

    Google Scholar 

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

    PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Zhang, H. et al. Delivery of mRNA vaccine with a lipid-like material potentiates antitumor efficacy through Toll-like receptor 4 signaling. Proc. Natl Acad. Sci. USA 118, e2005191118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Pastor, F. et al. An RNA toolbox for cancer immunotherapy. Nat. Rev. Drug Discov. 17, 751–767 (2018).

    CAS  PubMed  Google Scholar 

  82. Lang, F., Schrors, B., Lower, M., Tureci, O. & Sahin, U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat. Rev. Drug Discov. 21, 261–282 (2022). This review explains in detail the basic immune mechanisms involved in neoantigen vaccines, providing the readers with a deep and comprehensive understanding of how neoantigen vaccines work, the development process, the areas of application and their promise.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Blass, E. & Ott, P. A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 18, 215–229 (2021).

    PubMed  PubMed Central  Google Scholar 

  85. Conry, R. M. et al. Characterization of a messenger-RNA polynucleotide vaccine vector. Cancer Res. 55, 1397–1400 (1995).

    CAS  PubMed  Google Scholar 

  86. He, Q., Gao, H., Tan, D., Zhang, H. & Wang, J. Z. mRNA cancer vaccines: advances, trends and challenges. Acta Pharm. Sin. B 12, 2969–2989 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Boczkowski, D., Nair, S. K., Snyder, D. & Gilboa, E. Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J. Exp. Med. 184, 465–472 (1996).

    CAS  PubMed  Google Scholar 

  88. Anguille, S. et al. Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia. Blood 130, 1713–1721 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Van Tendeloo, V. F. et al. Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc. Natl Acad. Sci. USA 107, 13824–13829 (2010).

    PubMed  PubMed Central  Google Scholar 

  90. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00965224 (2013).

  91. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01291420 (2023).

  92. Lichtenegger, F. S. et al. Toll-like receptor 7/8-matured RNA-transduced dendritic cells as post-remission therapy in acute myeloid leukaemia: results of a phase I trial. Clin. Transl. Immunol. 9, e1117 (2020).

    Google Scholar 

  93. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01734304 (2018).

  94. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01983748 (2022).

  95. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04157127 (2022).

  96. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04837547 (2023).

  97. Beck, J. D. et al. mRNA therapeutics in cancer immunotherapy. Mol. Cancer 20, 69 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Koch, S. D. et al. A randomized, double-blind, placebo-controlled, phase I/II trial of RNActive®-vaccine cv9104 in patients with metastatic castrate-refractory prostate cancer (mcrpc): first results of the phase I part. J. Immunother. Cancer 2, p85 (2014).

    PubMed Central  Google Scholar 

  99. Kubler, H. et al. Self-adjuvanted mRNA vaccination in advanced prostate cancer patients: a first-in-man phase I/IIa study. J. Immunother. Cancer 3, 26 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01817738 (2013).

  101. Sebastian, M. et al. Phase Ib study evaluating a self-adjuvanted mRNA cancer vaccine (RNActive(R)) combined with local radiation as consolidation and maintenance treatment for patients with stage IV non-small cell lung cancer. BMC Cancer 14, 748 (2014).

    PubMed  PubMed Central  Google Scholar 

  102. Papachristofilou, A. et al. Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer. J. Immunother. Cancer 7, 38 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01915524 (2016).

  104. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02410733 (2023).

  105. Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020). This research demonstrates an intravenously administered mRNA vaccine targeting four non-mutated, tumour-associated antigens that are prevalent in melanoma for patients with advanced melanoma.

    CAS  PubMed  Google Scholar 

  106. BioNTech SE. BioNTech receives FDA fast track designation for its FixVac candidate BNT111 in advanced melanoma. GlobeNewswire https://www.globenewswire.com/news-release/2021/11/19/2338113/0/en/BioNTech-Receives-FDA-Fast-Track-Designation-for-its-FixVac-Candidate-BNT111-in-Advanced-Melanoma.html (2021).

  107. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04526899 (2023).

  108. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04534205 (2023).

  109. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04163094 (2022).

  110. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04382898 (2023).

  111. Benteyn, D., Heirman, C., Bonehill, A., Thielemans, K. & Breckpot, K. mRNA-based dendritic cell vaccines. Expert Rev. Vaccines 14, 161–176 (2015).

    CAS  PubMed  Google Scholar 

  112. Lecoultre, M., Dutoit, V. & Walker, P. R. Phagocytic function of tumor-associated macrophages as a key determinant of tumor progression control: a review. J. Immunother. Cancer 8, e001408 (2020).

    PubMed  PubMed Central  Google Scholar 

  113. Hirosue, S. & Dubrot, J. Modes of antigen presentation by lymph node stromal cells and their immunological implications. Front. Immunol. 6, 446 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Ruhland, M. K. et al. Visualizing synaptic transfer of tumor antigens among dendritic cells. Cancer Cell 37, 786–799.e5 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).

    CAS  PubMed  Google Scholar 

  116. Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    CAS  PubMed  Google Scholar 

  118. Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhang, R. et al. DP7-C-modified liposomes enhance immune responses and the antitumor effect of a neoantigen-based mRNA vaccine. J. Control. Release 328, 210–221 (2020).

    CAS  PubMed  Google Scholar 

  122. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02035956 (2020).

  123. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT04486378 (2023).

  124. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03289962 (2023).

  125. Cafri, G. et al. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J. Clin. Invest. 130, 5976–5988 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03480152 (2020).

  127. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03897881 (2022). The mRNA-4157/V940 used in this clinical trial gained the approval of breakthrough therapy designation by the FDA for the adjuvant treatment of patients with high-risk melanoma following complete resection.

  128. Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).

    CAS  PubMed  Google Scholar 

  129. Hashimoto, M. et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature 610, 173–181 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Briukhovetska, D. et al. Interleukins in cancer: from biology to therapy. Nat. Rev. Cancer 21, 481–499 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Berraondo, P. et al. Cytokines in clinical cancer immunotherapy. Br. J. Cancer 120, 6–15 (2019).

    CAS  PubMed  Google Scholar 

  132. Thayer, A. Interleukin-2 wins FDA market clearance. Chem. Eng. N. Arch. 70, 5 (1992).

    Google Scholar 

  133. Naing, A. et al. PEGylated IL-10 (Pegilodecakin) induces systemic immune activation, CD8+ T cell invigoration and polyclonal T cell expansion in cancer patients. Cancer Cell 34, 775–791.e3 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang, B. et al. Site-specific PEGylation of interleukin-2 enhances immunosuppression via the sustained activation of regulatory T cells. Nat. Biomed. Eng. 5, 1288–1305 (2021).

    PubMed  Google Scholar 

  135. Mansurov, A. et al. Collagen-binding IL-12 enhances tumour inflammation and drives the complete remission of established immunologically cold mouse tumours. Nat. Biomed. Eng. 4, 531–543 (2020).

    CAS  PubMed  Google Scholar 

  136. Qiao, J. et al. Targeting tumors with IL-10 prevents dendritic cell-mediated CD8+ T cell apoptosis. Cancer Cell 35, 901–915.e4 (2019).

    CAS  PubMed  Google Scholar 

  137. Gorby, C. et al. Engineered IL-10 variants elicit potent immunomodulatory effects at low ligand doses. Sci. Signal. 13, eabc0653 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Trotta, E. et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat. Med. 24, 1005–1014 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hochmann, S. et al. Evaluation of modified interferon alpha mRNA constructs for the treatment of non-melanoma skin cancer. Sci. Rep. 8, 12954 (2018).

    PubMed  PubMed Central  Google Scholar 

  140. Holder, P. G. et al. Engineering interferons and interleukins for cancer immunotherapy. Adv. Drug Deliv. Rev. 182, 114112 (2022).

    CAS  PubMed  Google Scholar 

  141. Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).

    CAS  PubMed  Google Scholar 

  142. Lai, I. et al. Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. J. Immunother. Cancer 6, 125 (2018).

    PubMed  PubMed Central  Google Scholar 

  143. Etxeberria, I. et al. Intratumor adoptive transfer of IL-12 mRNA transiently engineered antitumor CD8+ T cells. Cancer Cell 36, 613–629.e7 (2019).

    CAS  PubMed  Google Scholar 

  144. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03946800 (2023).

  145. Li, Y. et al. Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat. Cancer 1, 882–893 (2020). This works describes a single intratumoural administration of self-replicating IL12 mRNA lipid nanoparticles that can eradicate large established tumours and induce protective immune memory.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Liu, J. Q. et al. Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy. J. Control. Release 345, 306–313 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03739931 (2023).

  148. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03871348 (2022).

  149. Sherr, C. J. Principles of tumor suppression. Cell 116, 235–246 (2004).

    CAS  PubMed  Google Scholar 

  150. Soussi, T., Ishioka, C., Claustres, M. & Beroud, C. Locus-specific mutation databases: pitfalls and good practice based on the p53 experience. Nat. Rev. Cancer 6, 83–90 (2006).

    CAS  PubMed  Google Scholar 

  151. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Lee, Y. R., Chen, M. & Pandolfi, P. P. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat. Rev. Mol. Cell Biol. 19, 547–562 (2018).

    CAS  PubMed  Google Scholar 

  154. Ler, L. D. et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci. Transl Med. 9, eaai8312 (2017).

    PubMed  Google Scholar 

  155. Munoz-Fontela, C., Mandinova, A., Aaronson, S. A. & Lee, S. W. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat. Rev. Immunol. 16, 741–750 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    CAS  PubMed  Google Scholar 

  157. Lin, Y. X. et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci. Transl Med. 13, eaba9772 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Xiao, Y. et al. Combining p53 mRNA nanotherapy with immune checkpoint blockade reprograms the immune microenvironment for effective cancer therapy. Nat. Commun. 13, 758 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Pickar-Oliver, A. & Gersbach, C. A. The next generation of CRISPR–Cas technologies and applications. Nat. Rev. Mol. Cell Biol. 20, 490–507 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Price, B. D. & D’Andrea, A. D. Chromatin remodeling at DNA double-strand breaks. Cell 152, 1344–1354 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Ceccaldi, R., Rondinelli, B. & D’Andrea, A. D. Repair pathway choices and consequences at the double-strand break. Trends Cell Biol. 26, 52–64 (2016).

    CAS  PubMed  Google Scholar 

  163. Lieber, M. R., Ma, Y., Pannicke, U. & Schwarz, K. Mechanism and regulation of human non-homologous DNA end-joining. Nat. Rev. Mol. Cell Biol. 4, 712–720 (2003).

    CAS  PubMed  Google Scholar 

  164. Cornu, T. I., Mussolino, C. & Cathomen, T. Refining strategies to translate genome editing to the clinic. Nat. Med. 23, 415–423 (2017).

    CAS  PubMed  Google Scholar 

  165. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhang, H. X., Zhang, Y. & Yin, H. Genome editing with mRNA encoding ZFN, TALEN, and Cas9. Mol. Ther. 27, 735–746 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Liu, J. et al. Efficient delivery of nuclease proteins for genome editing in human stem cells and primary cells. Nat. Protoc. 10, 1842–1859 (2015).

    CAS  PubMed  Google Scholar 

  168. Chew, W. L. Immunity to CRISPR Cas9 and Cas12a therapeutics. Wiley Interdiscip. Rev. Syst. Biol. Med. 10, e1408 (2018).

    Google Scholar 

  169. Yin, H. et al. Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype. Nat. Biotechnol. 32, 551–553 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Miller, J. B. et al. Non-viral CRISPR/Cas gene editing in vitro and in vivo enabled by synthetic nanoparticle co-delivery of Cas9 mRNA and sgRNA. Angew. Chem. Int. Ed. 56, 1059–1063 (2017).

    CAS  Google Scholar 

  171. Rosenblum, D. et al. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy. Sci. Adv. 6, eabc9450 (2020). This work showcases the potential of using targeted lipid nanoparticles for the delivery of cas9 mRNA and sgRNAs to achieve precise in vivo genome editing, offering promising prospects for future cancer therapies.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Liu, S. et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR–Cas gene editing. Nat. Mater. 20, 701–710 (2021). The rational design of functional phospholipids presented in this work holds significant potential for advancing gene editing research and its therapeutic applications.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Wagner, D. L. et al. Immunogenicity of CAR T cells in cancer therapy. Nat. Rev. Clin. Oncol. 18, 379–393 (2021).

    PubMed  PubMed Central  Google Scholar 

  174. Atsavapranee, E. S., Billingsley, M. M. & Mitchell, M. J. Delivery technologies for T cell gene editing: applications in cancer immunotherapy. EBioMedicine 67, 103354 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Elsallab, M., Levine, B. L., Wayne, A. S. & Abou-El-Enein, M. CAR T-cell product performance in haematological malignancies before and after marketing authorisation. Lancet Oncol. 21, e104–e116 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl Med. 4, 132ra153 (2012).

    Google Scholar 

  177. MacKay, M. et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat. Biotechnol. 38, 233–244 (2020).

    CAS  PubMed  Google Scholar 

  178. Zhao, Y. et al. High-efficiency transfection of primary human and mouse T lymphocytes using RNA electroporation. Mol. Ther. 13, 151–159 (2006).

    CAS  PubMed  Google Scholar 

  179. Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Carlsten, M. et al. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. Front. Immunol. 7, 105 (2016).

    PubMed  PubMed Central  Google Scholar 

  181. Krug, C. et al. A GMP-compliant protocol to expand and transfect cancer patient T cells with mRNA encoding a tumor-specific chimeric antigen receptor. Cancer Immunol. Immunother. 63, 999–1008 (2014).

    CAS  PubMed  Google Scholar 

  182. Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).

    CAS  PubMed  Google Scholar 

  183. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01355965 (2017).

  184. Maus, M. V. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT01897415 (2017).

  186. Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).

    CAS  PubMed  Google Scholar 

  187. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02719782 (2018).

  188. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03060356 (2020).

  189. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04981691 (2021).

  190. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05302037 (2022).

  191. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02277522 (2017).

  192. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02624258 (2020).

  193. Svoboda, J. et al. Nonviral RNA chimeric antigen receptor-modified T cells in patients with Hodgkin lymphoma. Blood 132, 1022–1026 (2018).

    CAS  PubMed  Google Scholar 

  194. Tasian, S. K. et al. Optimized depletion of chimeric antigen receptor T cells in murine xenograft models of human acute myeloid leukemia. Blood 129, 2395–2407 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02623582 (2017).

  196. Mangala Prasad, V. et al. Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice. Cell 185, 641–653.e17 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Zhao, Z., Ukidve, A., Kim, J. & Mitragotri, S. Targeting strategies for tissue-specific drug delivery. Cell 181, 151–167 (2020).

    CAS  PubMed  Google Scholar 

  198. Zhang, P. et al. Cancer nanomedicine toward clinical translation: obstacles, opportunities, and future prospects. Med 4, 147–167 (2022).

    PubMed  Google Scholar 

  199. Rosenblum, D., Joshi, N., Tao, W., Karp, J. M. & Peer, D. Progress and challenges towards targeted delivery of cancer therapeutics. Nat. Commun. 9, 1410 (2018).

    PubMed  PubMed Central  Google Scholar 

  200. Ferdows, B. E. et al. RNA cancer nanomedicine: nanotechnology-mediated RNA therapy. Nanoscale 14, 4448–4455 (2022).

    CAS  PubMed  Google Scholar 

  201. Zhao, X. et al. Imidazole-based synthetic lipidoids for in vivo mRNA delivery into primary T lymphocytes. Angew. Chem. Int. Ed. 59, 20083–20089 (2020).

    CAS  Google Scholar 

  202. Ma, F. et al. Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection. Sci. Adv. 6, eabb4429 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Chen, J. et al. Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response. Proc. Natl Acad. Sci. USA 119, e2207841119 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Zou, Y. et al. Blood-brain barrier-penetrating single CRISPR-Cas9 nanocapsules for effective and safe glioblastoma gene therapy. Sci. Adv. 8, eabm8011 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Boehnke, N. et al. Massively parallel pooled screening reveals genomic determinants of nanoparticle delivery. Science 377, eabm5551 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Yang, Z. et al. Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nat. Biomed. Eng. 4, 69–83 (2020).

    CAS  PubMed  Google Scholar 

  207. Gurumurthy, C. B., Quadros, R. M. & Ohtsuka, M. Prototype mouse models for researching SEND-based mRNA delivery and gene therapy. Nat. Protoc. 17, 2129–2138 (2022).

    CAS  PubMed  Google Scholar 

  208. Segel, M. et al. Mammalian retrovirus-like protein PEG10 packages its own mRNA and can be pseudotyped for mRNA delivery. Science 373, 882–889 (2021). This research demonstrates that the mammalian retrovirus-like protein PEG10 can bind directly to its own mRNA and package it into extracellular virus-like capsids, potentially serving as an endogenous vector for mRNA-based gene therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Lokugamage, M. P. et al. Optimization of lipid nanoparticles for the delivery of nebulized therapeutic mRNA to the lungs. Nat. Biomed. Eng. 5, 1059–1068 (2021). This work reports that the optimized composition, molar ratios and structure of lipid nanoparticles can achieve nebulized delivery of an mRNA encoding a broadly neutralizing antibody for lung disease treatment.

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Vogel, A. B. et al. Self-amplifying RNA vaccines give equivalent protection against influenza to mRNA vaccines but at much lower doses. Mol. Ther. 26, 446–455 (2018).

    CAS  PubMed  Google Scholar 

  211. Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell 185, 1728–1744.e16 (2022). This study reports that circRNA vaccines enable effective protection against SARS-CoV-2 in mice and monkeys.

    CAS  PubMed  PubMed Central  Google Scholar 

  212. 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). This work reports the use of a self-amplifying mRNA-based neoantigen vaccine in combination with anti-PD1 and anti-CTLA4 in patients with advanced metastatic solid tumours.

    CAS  PubMed  Google Scholar 

  213. Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, 1001 (2020).

    Google Scholar 

  214. Ho, T. C. et al. Scaffold-mediated CRISPR-Cas9 delivery system for acute myeloid leukemia therapy. Sci. Adv. 7, eabg3217 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Hirano, S. et al. Structure of the OMEGA nickase IsrB in complex with omegaRNA and target DNA. Nature 610, 575–581 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Schuler, G., Hu, C. & Ke, A. Structural basis for RNA-guided DNA cleavage by IscB-omegaRNA and mechanistic comparison with Cas9. Science 376, 1476–1481 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Altae-Tran, H. et al. The widespread IS200/IS605 transposon family encodes diverse programmable RNA-guided endonucleases. Science 374, 57–65 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03468244 (2019).

  219. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03908671 (2019).

  220. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04161755 (2022).

  221. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03815058 (2023).

  222. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03948763 (2022).

  223. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03639714 (2023).

  224. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05141721 (2023).

  225. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05359354 (2022).

  226. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05198752 (2022).

  227. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05192460 (2023).

  228. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05227378 (2022).

  229. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05202561 (2022).

  230. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05456165 (2022).

  231. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT05533697 (2023).

  232. 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).

    PubMed  PubMed Central  Google Scholar 

  233. Fyfe, I. Treatment success in hereditary transthyretin amyloidosis. Nat. Rev. Neurol. 14, 509 (2018).

    PubMed  Google Scholar 

  234. Hess, P. R., Boczkowski, D., Nair, S. K., Snyder, D. & Gilboa, E. Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen. Cancer Immunol. Immunother. 55, 672–683 (2006).

    CAS  PubMed  Google Scholar 

  235. Perche, F. et al. Enhancement of dendritic cells transfection in vivo and of vaccination against B16F10 melanoma with mannosylated histidylated lipopolyplexes loaded with tumor antigen messenger RNA. Nanomedicine 7, 445–453 (2011).

    CAS  PubMed  Google Scholar 

  236. Le Moignic, A. et al. Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells. J. Control. Release 278, 110–121 (2018).

    PubMed  Google Scholar 

  237. Lv, H., Zhang, S., Wang, B., Cui, S. & Yan, J. Toxicity of cationic lipids and cationic polymers in gene delivery. J. Control. Release 114, 100–109 (2006).

    CAS  PubMed  Google Scholar 

  238. Landesman-Milo, D. & Peer, D. Toxicity profiling of several common RNAi-based nanomedicines: a comparative study. Drug Deliv. Transl. Res. 4, 96–103 (2014).

    CAS  PubMed  Google Scholar 

  239. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Tateshita, N. et al. Development of a lipoplex-type mRNA carrier composed of an ionizable lipid with a vitamin E scaffold and the KALA peptide for use as an ex vivo dendritic cell-based cancer vaccine. J. Control. Release 310, 36–46 (2019).

    CAS  PubMed  Google Scholar 

  241. 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). This study describes the creation of a combinatorial library consisting of ionizable lipid-like materials to identify effective mRNA delivery vehicles capable of facilitating mRNA delivery in vivo and producing potent and specific immune activation.

    CAS  PubMed  Google Scholar 

  242. Akinc, A. et al. A combinatorial library of lipid-like materials for delivery of RNAi therapeutics. Nat. Biotechnol. 26, 561–569 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. Love, K. T. et al. Lipid-like materials for low-dose, in vivo gene silencing. Proc. Natl Acad. Sci. USA 107, 1864–1869 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Paunovska, K. et al. Analyzing 2000 in vivo drug delivery data points reveals cholesterol structure impacts nanoparticle delivery. ACS Nano 12, 8341–8349 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Paunovska, K. et al. Nanoparticles containing oxidized cholesterol deliver mRNA to the liver microenvironment at clinically relevant doses. Adv. Mater. 31, e1807748 (2019).

    PubMed  PubMed Central  Google Scholar 

  246. Li, W. & Szoka, F. C. Jr. Lipid-based nanoparticles for nucleic acid delivery. Pharm. Res. 24, 438–449 (2007).

    PubMed  Google Scholar 

  247. Eygeris, Y., Gupta, M., Kim, J. & Sahay, G. Chemistry of lipid nanoparticles for RNA delivery. Acc. Chem. Res. 55, 2–12 (2022).

    CAS  PubMed  Google Scholar 

  248. Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. 49, 6288–6308 (2010).

    CAS  Google Scholar 

  249. Jokerst, J. V., Lobovkina, T., Zare, R. N. & Gambhir, S. S. Nanoparticle PEGylation for imaging and therapy. Nanomedicine 6, 715–728 (2011).

    CAS  PubMed  Google Scholar 

  250. Choi, H. Y. et al. Efficient mRNA delivery with graphene oxide-polyethylenimine for generation of footprint-free human induced pluripotent stem cells. J. Control. Release 235, 222–235 (2016).

    CAS  PubMed  Google Scholar 

  251. Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Release 228, 9–19 (2016).

    CAS  PubMed  Google Scholar 

  252. Uchida, S. et al. In vivo messenger RNA introduction into the central nervous system using polyplex nanomicelle. PLoS ONE 8, e56220 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work is supported by Basic Science Research Programs from the National Research Foundation of Korea (no. 2022R1C1C2007637 to S.K.), National Natural Science Foundation of China (no. 82122076 to N.K.), Harvard Medical School/Brigham and Women’s Hospital Department of Anaesthesiology Basic Scientist Grant (no. 2420 BPA075 to W.T.), Nanotechnology Foundation (no. 2022A002721 to W.T.), Gillian Reny Stepping Strong Center for Trauma Innovation Breakthrough Innovator Award (no. 113548 to W.T.), Center for Nanomedicine Research Fund (no. 2019A014810 to W.T.), and Farokhzad Family Distinguished Chair Foundation (no. 018129 to W.T.). W.T. is also a recipient of the Khoury Innovation Award (no. 2020A003219) and the American Heart Association (AHA) Collaborative Science Award (no. 2018A004190).

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Author notes

  1. These authors contributed equally: Chuang Liu, Qiangqiang Shi.

Authors and Affiliations

  1. Center for Nanomedicine and Department of Anaesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Chuang Liu, Qiangqiang Shi, Xiangang Huang, Seyoung Koo, Na Kong & Wei Tao

  2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China

    Qiangqiang Shi & Na Kong

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  1. Chuang Liu
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All authors researched data for the article, contributed substantially to discussion of the content, wrote, reviewed and edited the manuscript.

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Glossary

5′ and 3′ untranslated regions

(UTRs). Non-coding regulatory regions of mRNA that contain multiple regulatory elements.

5′ Cap

A specially altered nucleotide on the 5′ end of mRNA, which has a substantial role in the initiation of mRNA translation.

Chimeric antigen receptors

(CARs). Receptor proteins that combine antigen binding and T cell activation functions to drive T cells to target specific antigens.

Cytokines

A class of small proteins that modulate autocrine, paracrine and endocrine signalling.

Electroporation

A biological technique in which exogenous substances, such as drugs, DNA or mRNA, are transferred into a cell by applying an electrical field to the cell to increase the permeability of the cell membrane.

High-performance liquid chromatography

(HPLC). An analytical chemistry technique that relies on differences in the chemical interaction of each component of a sample with the sorbent material for the separation, identification and quantification of each component in a mixture.

Immune tolerant

Describes the inability of antigen-specific immune cells to be activated in response to antigen stimulation and to execute a normal immune response.

Ionizable phospholipid

(iPho). A lipid with an ionizable amino group, a phosphate head group and hydrophobic lipid tail; iPhos are positively charged at acidic pH to condense RNA into lipid nanoparticles, but are neutral at physiological pH to minimize toxicity.

Major histocompatibility complex

(MHC). A set of eukaryotic cell surface proteins that can be divided into MHC class I and II molecules.

Open reading frame

(ORF). The most crucial part of mRNA, which contains the coding sequence of the translated protein.

Peripheral blood mononuclear cells

(PBMCs). Blood cells with round nuclei that are generally comprised of lymphocytes (T cells, B cells, natural killer cells), monocytes and a small number of dendritic cells.

Poly(A) tail

A string of adenosine modifications to the 3′ end of mRNA, which plays a crucial part in preventing mRNA degradation and enhancing translation efficiency.

Regulatory T cells

(Treg cells). A subpopulation of T cells that regulate the immune system, maintain tolerance to self antigens and prevent autoimmune diseases.

RNA-dependent RNA polymerase

(RDRP). An enzyme that catalyses the replication of RNA from an RNA template.

Tumour microenvironment

(TME). The non-cancerous environment that surrounds tumour cells, including blood vessels, immune cells, fibroblasts, signalling molecules and extracellular matrix.

Tumour suppressors

Proteins that regulate cells during cell division and replication to prevent cancer.

Type I interferon

(IFN). A cytokine that fulfils an important role in inflammation, immunoregulation, tumour cell recognition and T cell responses.

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Liu, C., Shi, Q., Huang, X. et al. mRNA-based cancer therapeutics. Nat Rev Cancer 23, 526–543 (2023). https://doi.org/10.1038/s41568-023-00586-2

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