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Systemic tumour suppression via the preferential accumulation of erythrocyte-anchored chemokine-encapsulating nanoparticles in lung metastases

Abstract

Eliciting immune responses against primary tumours is hampered by their immunosuppressive microenvironment and by the greater inaccessibility of deeper intratumoural cells. However, metastatic tumour cells are exposed to highly perfused and immunoactive organs, such as the lungs. Here, by taking advantage of the preferential colocalization of intravenously administered erythrocytes with metastases in the lungs, we show that treatment with chemokine-encapsulating nanoparticles that are non-covalently anchored onto the surface of injected erythrocytes results in local and systemic tumour suppression in mouse models of lung metastasis. Such erythrocyte-anchored systemic immunotherapy led to the infiltration of effector immune cells into the lungs, in situ immunization without the need for exogenous antigens, inhibition of the progression of lung metastasis, and significantly extended animal survival and systemic immunity that suppressed the growth of distant tumours after rechallenge. Erythrocyte-mediated systemic immunotherapy may represent a general and potent strategy for cancer vaccination.

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Fig. 1: Engineering material properties of nanoparticles led to optimal targeted delivery.
Fig. 2: ImmunoBait anchored onto erythrocytes without causing obvious side effects to the carrier erythrocytes.
Fig. 3: EASI delivered ImmunoBait to lungs bearing metastases.
Fig. 4: EASI led to immunorestoration in lungs bearing metastases.
Fig. 5: EASI enhanced the infiltration of effector immune cells into the metastatic sites.
Fig. 6: EASI led to significant inhibition of the progression of lung metastasis and an improvement in survival.
Fig. 7: EASI resulted in in situ immunization and a systemic immune response.
Fig. 8: EASI led to systemic suppression of distant tumours.

Data availability

The main 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 too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

We thank D. Mooney for guidance. This work was financially supported by the Wyss Institute at Harvard University. The authors acknowledge funding from the National Institutes of Health (grant no. 1R01HL143806-01).

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Z.Z., A.U. and S.M. conceived and designed the experiments. Z.Z., A.U., V.K., A.F., D.C.P., Y.G., J.K., A.M., J.G. and M.A.E. performed the experiments. Z.Z., A.U., V.K., A.F., D.C.P., Y.G., J.K., A.M., J.G., M.A.E., V.M. and S.M. analysed and discussed results. Z.Z., A.U. and S.M. wrote the manuscript. All of the authors read, revised and approved the manuscript.

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Correspondence to Samir Mitragotri.

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S.M., A.U. and Z.Z. are inventors on a patent application with aspects related to this work filed by Harvard University (no. 62/858,478).

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Supplementary Figs. 1–39, Table 1, methods, discussion and references.

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Zhao, Z., Ukidve, A., Krishnan, V. et al. Systemic tumour suppression via the preferential accumulation of erythrocyte-anchored chemokine-encapsulating nanoparticles in lung metastases. Nat Biomed Eng (2020). https://doi.org/10.1038/s41551-020-00644-2

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