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Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery

Nature Materials volume 23, pages 1736–1747 (2024)Cite this article

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Abstract

Nanoparticles are promising for drug delivery applications, with several clinically approved products. However, attaining high nanoparticle accumulation in solid tumours remains challenging. Here we show that tumour cell-derived small extracellular vesicles (sEVs) block nanoparticle delivery to tumours, unveiling another barrier to nanoparticle-based tumour therapy. Tumour cells secrete large amounts of sEVs in the tumour microenvironment, which then bind to nanoparticles entering tumour tissue and traffic them to liver Kupffer cells for degradation. Knockdown of Rab27a, a gene that controls sEV secretion, decreases sEV levels and improves nanoparticle accumulation in tumour tissue. The therapeutic efficacy of messenger RNAs encoding tumour suppressing and proinflammatory proteins is greatly improved when co-encapsulated with Rab27a small interfering RNA in lipid nanoparticles. Together, our results demonstrate that tumour cell-derived sEVs act as a defence system against nanoparticle tumour delivery and that this system may be a potential target for improving nanoparticle-based tumour therapies.

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Fig. 1: Rab27a KO in tumour cells promotes the accumulation of LNPs in tumours.
Fig. 2: Binding of LNP to sEVs promotes the delivery of LNPs to liver Kupffer cells.
Fig. 3: sEVs act as a defence system against lipid nanoparticle-based mRNA delivery.
Fig. 4: Rab27a knockdown enhances LNP tumour delivery and the anti-tumour efficacy of Pten mRNA.
Fig. 5: Rab27a knockdown enhances the anti-tumour efficacy of a Sting mRNA.
Fig. 6: Tumour cell-derived extracellular vesicles act as a defence system against other nanoparticles and tumour therapeutics.

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Data availability

All relevant data of this article are available within the paper and its Supplementary Information files. A dataset is provided with this paper. Transcriptomics sequencing data is available from the Sequence Read Archive under accession code PRJNA1086632. Mouse single-cell RNA sequencing datasets were downloaded from Gene Expression Omnibus (GSE109774). The images in Supplementary Figs. 19, 20, 23 and 24b were downloaded from The Human Protein Atlas (primary publication: Uhlén M., Fagerberg L., Hallström B.M., et al. Science, 2015, 347(6220): 1260419.). Source data are provided with this paper.

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Acknowledgements

M.J.M. acknowledges support from a US National Institutes of Health (NIH) Director’s New Innovator Award (DP2 TR002776), a Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Science Foundation CAREER Award (CBET-2145491) and an American Cancer Society Research Scholar grant (RSG-22-122-01-ET). W.G. acknowledges supports from NIH R35 GM141832 and NCI P50 CA261608.

Author information

Author notes

  1. These authors contributed equally: Ningqiang Gong, Wenqun Zhong, Mohamad-Gabriel Alameh.

Authors and Affiliations

  1. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Ningqiang Gong, Xuexiang Han, Lulu Xue, Rakan El-Mayta, Alex G. Hamilton, Dongyoon Kim, Junchao Xu & Michael J. Mitchell

  2. Division of Life Sciences and Medicine, Center for BioAnalytical Chemistry, Hefei National Research Center for Physical Science at the Microscale, University of Science and Technology of China, Hefei, China

    Ningqiang Gong

  3. Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA

    Wenqun Zhong, Zhiyuan Qin, Fengyuan Xu, Junhyong Kim & Wei Guo

  4. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Mohamad-Gabriel Alameh & Drew Weissman

  5. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Gan Zhao & Andrew E. Vaughan

  6. Department of Chemistry, Tsinghua University, Beijing, China

    Xucong Teng & Jinghong Li

  7. Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China

    Xing-Jie Liang

  8. Penn institute for RNA innovation, University of Pennsylvania, Philadelphia, PA, USA

    Drew Weissman & Michael J. Mitchell

  9. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  10. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  11. Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

  12. Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael J. Mitchell

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Contributions

N.G., W.Z. M.-G.A., D.W., W.G. and M.J.M. conceived and designed the experiments. N.G., W.Z., M.-G.A., X.H., L.X., R.E.-M., G.Z., Z.Q., F.X., A.G.H, D.K. and J.X. performed the experiments, N.G., W.Z. L.X., X.H. and X.T. analysed the data. N.G., W.Z. M.-G.A., D.W., W.G. and M.J.M. wrote and edited the manuscript. J.L. and X.-J.L. were involved in discussion. D.W., W.G. and M.J.M. supervised the entire project. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Drew Weissman, Wei Guo or Michael J. Mitchell.

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Competing interests

N.G., M.J.M., W.Z. and W.G. have filed a patent (Lipid nanoparticle (LNP) compositions and methods for delivering therapeutic agents to tumour cells) related to this paper.

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Extended data

Extended Data Fig. 1 LNPs delivering siRab27a and mSTING-miR-122 do not induce systemic toxicity.

1x106 MC38 cells were s.c. injected into the right flank of mice at day 0. At day 8, the tumour size reached 50 mm3. Mice were then treated with the following LNPs: 1) LNP co-encapsulating siRab27a and scrambled mRNA; 2) LNP co-encapsulating scrambled siRNA and mSTING-miR-122; or 3) LNP co-encapsulating siRab27a and mSTING-miR-122. These LNPs were i.v. injected (0.25mg/kg) into mice at days 7, 9, 11, 13, and 15. PBS injections into mice at different time points were used as a control group. When tumour sizes in the PBS group reached 1500 mm3 (day 20), mice were euthanized and ALT (a), AST (b), IL-6 (c), and IL-12p70 (d) in mouse blood were measured. e, H&E staining of mouse livers collected from different groups. f, H&E staining of major mouse organs collected from the PBS group and the STING-miR-122 + siRab27a group at day 50. Data in a-d was shown as mean ± s.d. (n=5 biologically independent samples). One-way ANOVA was used to determine statistical differences. e and f, Experiments were repeated independently 3 times with similar results.

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Gong, N., Zhong, W., Alameh, MG. et al. Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery. Nat. Mater. 23, 1736–1747 (2024). https://doi.org/10.1038/s41563-024-01961-6

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