Lipid Nanoparticle-mediated Lymph Node-targeting Delivery of MRNA Cancer Vaccine Elicits Robust CD8 T Cell Response

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2022 Aug 15

PMID 35969778

Authors

Jinjin Chen

Zhongfeng Ye

Changfeng Huang

Min Qiu

Donghui Song

Yamin Li

Qiaobing Xu

Affiliations

Soon will be listed here.

Abstract

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8 T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Citing Articles

Current clinical applications of RNA-LNPs in cancer: a promising horizon for targeted therapies.

Hussain M, Khan G EXCLI J. 2025; 24:321-324.

PMID: 40071028 PMC: 11895062. DOI: 10.17179/excli2025-8132.

Recent advances and perspectives on the development of circular RNA cancer vaccines.

Gong Z, Hu W, Zhou C, Guo J, Yang L, Wang B NPJ Vaccines. 2025; 10(1):41.

PMID: 40025038 PMC: 11873252. DOI: 10.1038/s41541-025-01097-x.

Developing mRNA Nanomedicines with Advanced Targeting Functions.

Wang J, Cai L, Li N, Luo Z, Ren H, Zhang B Nanomicro Lett. 2025; 17(1):155.

PMID: 39979495 PMC: 11842722. DOI: 10.1007/s40820-025-01665-9.

Cancer vaccines: current status and future directions.

Zhou Y, Wei Y, Tian X, Wei X J Hematol Oncol. 2025; 18(1):18.

PMID: 39962549 PMC: 11834487. DOI: 10.1186/s13045-025-01670-w.

Targeting vaccines to dendritic cells by mimicking the processing and presentation of antigens in xenotransplant rejection.

Wang J, Zhang Y, Jia Y, Xing H, Xu F, Xia B Nat Biomed Eng. 2025; 9(2):201-214.

PMID: 39948171 DOI: 10.1038/s41551-025-01343-6.

References

Chen J, Chen J, Xu Q . Current Developments and Challenges of mRNA Vaccines. Annu Rev Biomed Eng. 2022; 24:85-109. DOI: 10.1146/annurev-bioeng-110220-031722. View

Li Y, Su Z, Zhao W, Zhang X, Momin N, Zhang C . Multifunctional oncolytic nanoparticles deliver self-replicating IL-12 RNA to eliminate established tumors and prime systemic immunity. Nat Cancer. 2021; 1(9):882-893. PMC: 8386348. DOI: 10.1038/s43018-020-0095-6. View

Yunna C, Mengru H, Lei W, Weidong C . Macrophage M1/M2 polarization. Eur J Pharmacol. 2020; 877:173090. DOI: 10.1016/j.ejphar.2020.173090. View

Hassett K, Benenato K, Jacquinet E, Lee A, Woods A, Yuzhakov O . Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. Mol Ther Nucleic Acids. 2019; 15:1-11. PMC: 6383180. DOI: 10.1016/j.omtn.2019.01.013. View

Vasievich E, Ramishetti S, Zhang Y, Huang L . Trp2 peptide vaccine adjuvanted with (R)-DOTAP inhibits tumor growth in an advanced melanoma model. Mol Pharm. 2011; 9(2):261-8. PMC: 3273554. DOI: 10.1021/mp200350n. View

Dienz O, Rincon M . The effects of IL-6 on CD4 T cell responses. Clin Immunol. 2008; 130(1):27-33. PMC: 2660866. DOI: 10.1016/j.clim.2008.08.018. View

Linares-Fernandez S, Lacroix C, Exposito J, Verrier B . Tailoring mRNA Vaccine to Balance Innate/Adaptive Immune Response. Trends Mol Med. 2019; 26(3):311-323. DOI: 10.1016/j.molmed.2019.10.002. View

Pardi N, Hogan M, Weissman D . Recent advances in mRNA vaccine technology. Curr Opin Immunol. 2020; 65:14-20. DOI: 10.1016/j.coi.2020.01.008. View

Yoshida K, Okamoto M, Sasaki J, Kuroda C, Ishida H, Ueda K . Anti-PD-1 antibody decreases tumour-infiltrating regulatory T cells. BMC Cancer. 2020; 20(1):25. PMC: 6950856. DOI: 10.1186/s12885-019-6499-y. View

10.

Zhang N, Li X, Deng Y, Zhao H, Huang Y, Yang G . A Thermostable mRNA Vaccine against COVID-19. Cell. 2020; 182(5):1271-1283.e16. PMC: 7377714. DOI: 10.1016/j.cell.2020.07.024. View

11.

Moss K, Popova P, Hadrup S, Astakhova K, Taskova M . Lipid Nanoparticles for Delivery of Therapeutic RNA Oligonucleotides. Mol Pharm. 2019; 16(6):2265-2277. DOI: 10.1021/acs.molpharmaceut.8b01290. View

12.

Kariko K, Muramatsu H, Welsh F, Ludwig J, Kato H, Akira S . Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008; 16(11):1833-40. PMC: 2775451. DOI: 10.1038/mt.2008.200. View

13.

Qiu M, Tang Y, Chen J, Muriph R, Ye Z, Huang C . Lung-selective mRNA delivery of synthetic lipid nanoparticles for the treatment of pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A. 2022; 119(8). PMC: 8872770. DOI: 10.1073/pnas.2116271119. View

14.

Zhi D, Zhang S, Wang B, Zhao Y, Yang B, Yu S . Transfection efficiency of cationic lipids with different hydrophobic domains in gene delivery. Bioconjug Chem. 2010; 21(4):563-77. DOI: 10.1021/bc900393r. View

15.

Majzner R, Mackall C . Tumor Antigen Escape from CAR T-cell Therapy. Cancer Discov. 2018; 8(10):1219-1226. DOI: 10.1158/2159-8290.CD-18-0442. View

16.

Kauffman K, Mir F, Jhunjhunwala S, Kaczmarek J, Hurtado J, Yang J . Efficacy and immunogenicity of unmodified and pseudouridine-modified mRNA delivered systemically with lipid nanoparticles in vivo. Biomaterials. 2016; 109:78-87. PMC: 5267554. DOI: 10.1016/j.biomaterials.2016.09.006. View

17.

Wang M, Zuris J, Meng F, Rees H, Sun S, Deng P . Efficient delivery of genome-editing proteins using bioreducible lipid nanoparticles. Proc Natl Acad Sci U S A. 2016; 113(11):2868-73. PMC: 4801296. DOI: 10.1073/pnas.1520244113. View

18.

Maier M, Jayaraman M, Matsuda S, Liu J, Barros S, Querbes W . Biodegradable lipids enabling rapidly eliminated lipid nanoparticles for systemic delivery of RNAi therapeutics. Mol Ther. 2013; 21(8):1570-8. PMC: 3734658. DOI: 10.1038/mt.2013.124. View

19.

Qiu M, Glass Z, Chen J, Haas M, Jin X, Zhao X . Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of . Proc Natl Acad Sci U S A. 2021; 118(10). PMC: 7958351. DOI: 10.1073/pnas.2020401118. View

20.

Hou X, Zaks T, Langer R, Dong Y . Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021; 6(12):1078-1094. PMC: 8353930. DOI: 10.1038/s41578-021-00358-0. View