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

Ningqiang Gong; Wenqun Zhong; Mohamad-Gabriel Alameh; Xuexiang Han; Lulu Xue; Rakan El-Mayta; Gan Zhao; Andrew E Vaughan; Zhiyuan Qin; Fengyuan Xu; Alex G Hamilton; Dongyoon Kim; Junchao Xu; Junhyong Kim; Xucong Teng; Jinghong Li; Xing-Jie Liang; Drew Weissman; Wei Guo; Michael J Mitchell

doi:10.1038/s41563-024-01961-6

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

Nat Mater. 2024 Sep 2. doi: 10.1038/s41563-024-01961-6. Online ahead of print.

Authors

Ningqiang Gong^#^{1

2}, Wenqun Zhong^#³, Mohamad-Gabriel Alameh^#⁴, Xuexiang Han¹, Lulu Xue¹, Rakan El-Mayta¹, Gan Zhao⁵, Andrew E Vaughan⁵, Zhiyuan Qin³, Fengyuan Xu³, Alex G Hamilton¹, Dongyoon Kim¹, Junchao Xu¹, Junhyong Kim³, Xucong Teng⁶, Jinghong Li⁶, Xing-Jie Liang⁷, Drew Weissman^{8

9}, Wei Guo¹⁰, Michael J Mitchell^{11

12

13

14

15

16}

Affiliations

¹ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
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.
³ Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁶ Department of Chemistry, Tsinghua University, Beijing, China.
⁷ Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China.
⁸ Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
⁹ Penn institute for RNA innovation, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁰ Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹¹ Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹² Penn institute for RNA innovation, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹³ Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁴ Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁵ Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
¹⁶ Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].

^# Contributed equally.

PMID: 39223270
DOI: 10.1038/s41563-024-01961-6

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.

Abstract

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