Abstract
The success of personalized cancer immunotherapy depends on the initial tumour antigenic presentation to dendritic cells and macrophages. Tumour-derived extracellular vesicles (TEVs) contain abundant tumour antigenic molecules. The presence of anti-phagocytotic signals such as cluster of differentiation 47 (CD47) on the surface of the TEVs, however, leads to evasion of the same dendritic cells and macrophages. Here we show that iron oxide hydroxide nanocomposites can successfully mask TEV surfaces and unblock phagocytosis without affecting extracellular vesicles’ elicited immune goals. After internalization, the mask disintegrates in the lysosome, releasing the tumour antigenic cargo. This triggers antigen presentation and promotes dendritic cell activation and maturation and macrophage reprogramming in animal models, leading to a drastic reduction of tumour volume and metastasis, and in human malignant pleural effusion clinical samples. This straightforward masking strategy eliminates the ubiquitous anti-phagocytosis block found in clinical samples and can be applied universally across all patient-specific TEVs as tumour antigenic agents for enhanced immunotherapy.
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Data availability
The authors declare that all data supporting the results in this study are available within the paper and Supplementary Information. Source data for Figs. 1–5 and Supplementary Figs. 1–50 are available in separate source data files. Source data are provided with this paper.
Code availability
The custom code used for the statistical analyses is available from the corresponding author upon reasonable request.
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Acknowledgements
This work was supported by the Leading-edge Technology Programme of Jiangsu Natural Science Foundation (BK20212012), Natural Science Foundation (22207056 and 62288102) and the Natural Science Foundation of Jiangsu Province (BK20210580). This work was also supported by the CAS Key Laboratory of Nano-Bio Interface (21NBI01) and Key Laboratory of Nanodevices and Applications (22ZS06). We thank H. Zhou (The First Affiliated Hospital of Soochow University) for the assistance of clinical MPE collection. We thank K. P. Wang and J. X. Du for their help in animal experiments.
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Conceptualization was carried out by X.G.D. and D.T.L. Analysis was carried out by X.G.D. and D.T.L. Methodology was planned by J.J.Z., S.S.W., X.W., Z.Y.W., M.W., Y.C. and K.F.P. Investigation was performed by J.J.Z., S.S.W., L.X.W., H.J.Z., F.P., Y.C., J.C. and R.J.P. Visualization was performed by J.J.Z., X.W., Z.Y.W. and M.W. Funding acquisition was carried out by X.G.D. and L.H.W. Project administration was performed by X.G.D. and L.H.W. Supervision was carried out by X.G.D. and L.H.W. Writing of the original draft was performed by J.J.Z., X.G.D. and D.T.L. Writing, review and editing was carried out by J.J.Z., X.G.D. and D.T.L.
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Nature Nanotechnology thanks Hui Qian, Tadashi Yokosuka and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Ding, X., Zhang, J., Wan, S. et al. Non-discriminating engineered masking of immuno-evasive ligands on tumour-derived extracellular vesicles enhances tumour vaccination outcomes. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01783-2
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DOI: https://doi.org/10.1038/s41565-024-01783-2
