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Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers

Nature Biomedical Engineering (2024)Cite this article

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Abstract

Messenger RNA vaccines lack specificity for dendritic cells (DCs)—the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid–nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

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Fig. 1: Design and characterization of a VLP-based SARS-CoV-2 mRNA vaccine.
Fig. 2: VLP–S-mut mRNA induced robust and durable spike-specific antibody responses.
Fig. 3: DVLP–S-mut mRNA vaccine enhanced spike-specific immune response.
Fig. 4: DVLP–S-mut mRNA improved spike-specific humoral and T-cell responses compared with LNP–mRNA.
Fig. 5: In vivo characterization of the biodistribution and DC-targeting capability of DVLPs.
Fig. 6: The DVLP–S-mut mRNA vaccine efficiently protected hACE2-transgenic mice from SARS-CoV-2 challenge.
Fig. 7: The DVLP-mediated delivery of gB1 and gD1 mRNA efficiently protected mice from HSV-1 infection.

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Data availability

Source data for the figures are available from figshare51 at https://doi.org/10.6084/m9.figshare.24516694. The raw and analysed datasets generated during the study are available for research purposes from the corresponding authors on reasonable request. Source data are provided with this paper.

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Acknowledgements

Y.C. is supported by the National Key R&D Program of China (2022YFC3400205), the National Natural Science Foundation of China (31971364) and Shanghai Jiao Tong University Scientific and Technological Innovation Funds (AF4150049). J.H. is supported by the National Natural Science Foundation of China (81970766 and 82171102) and the Shanghai Innovation Development Program (2020-RGZN-02033). T.Y. is supported by the National Key R&D Program of China (2019YFA0904400) and the National Natural Science Foundation of China (81822027 and 81630090). S.T. is supported by the National Natural Science Foundation of China (31970130) and the National Key R&D Program of China (2020YFE0202200).

Author information

Author notes

  1. These authors contributed equally: Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Xiaoyuan Wang.

Authors and Affiliations

  1. Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China

    Di Yin, Yiye Zhong, Sikai Ling, Sicong Lu, Zhuofan Jiang, Jie Wang, Yao Dai, Qijing Huang, Junsong Chen, Ziying Li, Yang Li, Zhijue Xu, Hewei Jiang, Yan Zhang, Lintai Da, Ze-guang Han, Sheng-ce Tao, Ruijiao Dong & Yujia Cai

  2. BDGENE Therapeutics, Shanghai, China

    Sikai Ling & Xiaoyuan Wang

  3. MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Xiaolong Tian & Tianlei Ying

  4. MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China

    Xingbo Wang

  5. Department of Ophthalmology and Vision Science, Shanghai Eye, Ear, Nose and Throat Hospital, Fudan University, Shanghai, China

    Yuqing Wu, Jianjiang Xu & Jiaxu Hong

  6. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China

    Yi Shi

  7. National Beijing Center for Drug Safety Evaluation and Research, State Key Laboratory of Medical Countermeasures and Toxicology, Institute of Pharmacology and Toxicology, Academy of Military Sciences, Beijing, China

    Quanjun Wang

  8. CAS Key Laboratory of Special Pathogens and Biosafety, Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China

    Wei Hong, Heng Xue & Hang Yang

  9. University of Chinese Academy of Sciences, Beijing, China

    Wei Hong, Heng Xue & Hang Yang

  10. Hubei Jiangxia Laboratory, Wuhan, China

    Hang Yang

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  1. Di Yin
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Contributions

Y.C. conceived the study and designed the experiments; D.Y., Y. Zhong, S. Ling, S. Lu, Xiaoyuan Wang, Z.J., J.W., Y.D., X.T., Q.H., Xingbo Wang, J.C., Z.L., Y.L., Z.X., H.J., Y.W., Y.S., Q.W., J.X., W.H., H.X., H.Y., Y. Zhang, L.D., Z.H., S.T., R.D., T.Y. and J.H. performed the experiments or provided essential experimental resources; all the authors analysed the data; Y. Zhong, D.Y., S. Ling, and Y.C. wrote the manuscript with help from all the authors.

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Correspondence to Jiaxu Hong or Yujia Cai.

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Y.C. is a co-founder and advisor of BDGENE Therapeutics. The other authors declare no competing interests.

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Yin, D., Zhong, Y., Ling, S. et al. Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01208-4

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