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

Nature Biomedical Engineering volume 9, pages 201–214 (2025)Cite this article

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Abstract

Targeting the delivery of vaccines to dendritic cells (DCs) is challenging. Here we show that, by mimicking the fast and strong antigen processing and presentation that occurs during the rejection of xenotransplanted tissue, xenogeneic cell membrane-derived vesicles exposing tissue-specific antibodies can be leveraged to deliver peptide antigens and mRNA-encoded antigens to DCs. In mice with murine melanoma and murine thymoma, xenogeneic vesicles encapsulating a tumour-derived antigenic peptide or coated on lipid nanoparticles encapsulating an mRNA coding for a tumour antigen elicited potent tumour-specific T-cell responses that inhibited tumour growth. Mice immunized with xenogeneic vesicle-coated lipid nanoparticles encapsulating an mRNA encoding for the spike protein of severe acute respiratory syndrome coronavirus 2 elicited titres of anti-spike receptor-binding domain immunoglobulin G and of neutralizing antibodies that were approximately 32-fold and 6-fold, respectively, those elicited by a commercialized mRNA–lipid nanoparticle vaccine. The advantages of mimicking the biological recognition between immunoglobulin G on xenogeneic vesicles and fragment crystallizable receptors on DCs may justify the assessment of the safety risks of using animal-derived biological products in humans.

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Fig. 1: IgG binding donates XMV DC targeting capacity.
Fig. 2: XMVs enhance DC maturation and cross-presentation.
Fig. 3: XMVs deliver antigen peptide specifically to LNs and elicit potent immune responses.
Fig. 4: XMV–Ag induces potent antitumour T-cell responses.
Fig. 5: XMV coating on LNP delivering an mRNA-encoding antigen for cancer and COVID-19 vaccination.

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Data availability

The data supporting the results in this study are available within the paper and its Supplementary Information. 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

This work was supported by the National Key Research & Development Program of China (grant nos. 2021YFA1201000, 2023YFC2605000, 2024YFA1208301, 2024YFA1212400), National Natural Science Foundation of China (NSFC) (grant nos. 32030060, 82430067, GG9100007028, 22477118). The authors also appreciate the support by the Science Fund for Creative Research Groups of Nature Science Foundation of Hebei Province (B2021201038). This work was also supported by the NSFC (grant no. 82104105), China Postdoctoral Science Foundation 2021M693966. We thank D. Zhang and J. Lian (Core Facility, Center of Biomedical Analysis, Tsinghua University) for technical support with whole LN immunolabeling, tissue clearing, imaging and computational analysis.

Author information

Author notes

  1. These authors contributed equally: Jinjin Wang, Yuxuan Zhang.

Authors and Affiliations

  1. CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, China

    Jinjin Wang, Yuxuan Zhang, Yaru Jia, Haonan Xing, Fengfei Xu, Bozhang Xia, Wenjia Lai, Yuan Yuan, Xianlei Li, Shaobo Shan, Junge Chen & Xing-Jie Liang

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

    Jinjin Wang, Yuxuan Zhang, Fengfei Xu, Bozhang Xia & Xing-Jie Liang

  3. State Key Laboratory of New Pharmaceutical Preparations and Excipients, Hebei University, Baoding, China

    Yaru Jia, Jinchao Zhang & Xing-Jie Liang

  4. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China

    Haonan Xing & Aiping Zheng

  5. School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, China

    Weisheng Guo & Xing-Jie Liang

  6. Department of Chemistry, Center for BioAnalytical Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, New Cornerstone Science Institute, Tsinghua University, Beijing, China

    Jinghong Li

  7. Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, China

    Ningqiang Gong

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Contributions

J.W., N.G. and X.-J.L. conceived and designed the experiments. J.W., N.G., Y.Z., H.X., Y.J., W.L., X.L., F.X. and B.X. performed the experiments. J.W., X.-J.L., Y.Y. and S.S. analysed the results. J.C., Y.Y., X.L., W.G., S.S., J.Z. and A.Z. provided suggestions and technical support. J.L. provided support for the use of light-sheet microscopy for LN imaging and contributed to the discussion and guidance on the characterization of the vaccine. J.W., N.G. and X.-J.L. wrote the manuscript. N.G. and X.-J.L. supervised the entire project. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Ningqiang Gong or Xing-Jie Liang.

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Competing interests

J.W., N.G. and X.-J.L. have filed a patent application related to this study. The other authors declare no competing interests.

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Extended data

Extended Data Fig. 1 IgG modified liposome targets DCs.

a, Illustration of the preparation of liposomes (LIP) and IgG-modified liposomes (LIP-IgG). b, Hydrodynamic diameter and Zeta-potential of LIP and LIP-IgG. c, Quantitative analysis of the uptake of FITC labeled LIP- or LIP-IgG by different cells (3T3, HUVEC, RAW 264.7, DC2.4) using flow cytometry. d, Quantitative analysis of the uptake of LIP, LIP-IgG, or Fc-fragment modified Lip (LIP-Fc) by DC2.4 cells. e-f, DC2.4 cells were pretreated with various concentrations of IgG (e) or Fc fragment (f) and then FITC labeled LIP-IgG were added. After 2 h incubation, mean fluorescence intensity (MFI) of DC2.4 cells were determined using flow cytometry. Data are presented as mean ±s.d., n = 3 independent biological samples per group, statistical differences in c were determined using two-way ANOVA with Tukey’s test for multiple comparison.

Source data

Extended Data Fig. 2 IgG binding to XMVs increases DC uptake.

Mouse subcutaneous tissue homogenate was prepared and centrifuged to remove cells. The supernatant was collected and exploited to treat XMVs (30 min, 37 °C). After that, the XMVs were collected by centrifugation and washed with PBS. a, A representative TEM image of XMV after stained with an anti-IgG antibody-conjugated to gold bead. Scare bar, 50 nm. Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to identify and quantify the components of the protein corona. Classifications of components of the proteins (b) and their isoelectric point (pI) (c) of the top 21 abundant proteins. d, Gating strategies for analyzing antibody binding to XMVs. e, The binding of IgG, IgA, or IgM to XMVs after XMVs were incubated with subcutaneous tissue homogenate, analyzed using a CytoFLEX nanoflow cytometry. f, XMVs from different cell lines (PED, Vero) were used to prepare XMV-Ag. Mouse IgG was mixed with XMV-Ag for 30 min to form IgG-XMV-Ag. Various XMV-Ag, AUV-Ag (AUVs were derived from mouse RBC cells), or Lip- Ag were used to treat DC2.4 cells. After 2 h, The uptake of the antigen peptide by DC2.4 were determined using flow cytometry. g, XMV-Ag were preincubated with different amounts of IgG and then were added to DC2.4 cells. After 2 h, MFI of DC2.4 cells were determined using flow cytometry. h, XMV-Ag or XMV-Ag with IgG-preincubation were used to treat DC2.4 cells in the absence or present of FcR blockade. i, BMDCs were incubated with the XMV-Ag for 24 h and the presentation of SIINFEKL peptide on DC surface were stained using a H-2 K(b) OVA (SIINFEKL) antibody. After that, the cells were observed using a confocal microscopy. Green, Ag/MHC-I; blue, nuclei. Data are presented as mean ±s.d. and statistical differences in f were determined using one-way ANOVA with Tukey’s test for multiple comparison.

Source data

Extended Data Fig. 3 XMV-Ag targets DCs and promotes DC maturation in vivo.

Mice were subcutaneously injected with FITC labeled XMV-Ag at 0 h. After 24 h, the LNs were collected and the percentages of cellular uptake of FITC-XMV-Ag in LNs were determined using flow cytometry. a. Flow cytometry analysis of cellular uptake of XMV-Ag in LNs. Representative flow dot plots (left) and the percentages of XMV-Ag uptake by various cells in LNs (right) are shown. b. Gating strategy for flow cytometry analysis of DC subtypes such as cDC1(CD317-B220-CD11c+MHC-II+XCR1+), cDC2(CD317-B220-CD11c+MHC-II+CD172+) and pDC (CD317+B220+) in LNs. Mice were treated with XMV-Ag for 24 h and the percentages of CD11c+ CD40+ DCs (c) and CD11c+ CD86+ DCs (d) in LNs were determined using flow cytometry. Data are presented as mean ± s.d. Data in a, c-d, n = 3 independent biological samples per group.

Source data

Extended Data Fig. 4 XMV-Ag induces T-cell immune responses.

a, Flow cytometry analysis of OVA tetramer+CD8+ T cells in total blood immune cells. b, Percentages of IFN-γ+ cells in splenic CD8+CD44+ T cells from mice treated with three vaccinations of XMV-Ag, AUV-Ag, LIP-Ag, free Ag, or PBS. Representative flow dot plots (c-d) and quantifications (e-f) of memory cells in CD4+ or CD8+ T cells, naive T cells in CD4+ or CD8+ T cells in spleen cells after three-doses of XMV-Ag, AUV-Ag, LIP-Ag, free Ag, or PBS. Data are presented as mean ±s.d.(n = 4), statistical differences were determined using one-way ANOVA with Tukey’s test for multiple comparison.

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Wang, J., Zhang, Y., Jia, Y. et al. Targeting vaccines to dendritic cells by mimicking the processing and presentation of antigens in xenotransplant rejection. Nat. Biomed. Eng 9, 201–214 (2025). https://doi.org/10.1038/s41551-025-01343-6

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