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The lipid-binding D4 domain of perfringolysin O facilitates the active loading of exogenous cargo into extracellular vesicles

Abayomi Emmanuel Opadele

Abayomi Emmanuel Opadele

Laboratory for Molecular and Cellular Dynamics Research, Graduate School of Biomedical Science and Engineering, Hokkaido University, Sapporo, Japan

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Soichiro Nishioka

Soichiro Nishioka

Global Center for Biomedical Science and Engineering (GCB), Faculty of Medicine, Hokkaido University, Sapporo, Japan

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Ping-Hsiu Wu

Ping-Hsiu Wu

Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taiwan

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Quynh-Thu Le

Quynh-Thu Le

Department of Radiation Oncology, Stanford University School of Medicine, CA, USA

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Hiroki Shirato

Hiroki Shirato

Global Center for Biomedical Science and Engineering (GCB), Faculty of Medicine, Hokkaido University, Sapporo, Japan

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Jin-Min Nam

Corresponding Author

Jin-Min Nam

Global Center for Biomedical Science and Engineering (GCB), Faculty of Medicine, Hokkaido University, Sapporo, Japan

Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Japan

Correspondence

J.-M. Nam, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto City, Kyoto 606-8501, Japan

Tel: +81 75 753 7567

E-mail: [email protected]

and

Y. Onodera, Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, N15W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan

Tel: +81 11 706 5076

E-mail: [email protected]

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Yasuhito Onodera

Corresponding Author

Yasuhito Onodera

Global Center for Biomedical Science and Engineering (GCB), Faculty of Medicine, Hokkaido University, Sapporo, Japan

Correspondence

J.-M. Nam, Division of Systemic Life Science, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto City, Kyoto 606-8501, Japan

Tel: +81 75 753 7567

E-mail: [email protected]

and

Y. Onodera, Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, N15W7 Kita-ku, Sapporo, Hokkaido 060-8638, Japan

Tel: +81 11 706 5076

E-mail: [email protected]

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First published: 09 February 2024
Edited by Amitabha Chattopadhyay

Abstract

Whereas extracellular vesicles (EVs) have been engineered for cargo loading, innovative strategies for it can still be developed. Here, we describe domain 4 (D4), a cholesterol-binding domain derived from perfringolysin O, as a viable candidate for EV cargo loading. D4 and its mutants localized to the plasma membrane and the membranes of different vesicular structures in the cytoplasm, and facilitate the transport of proteins of interest (POIs) into EVs. D4-EVs were internalized by recipient cells analogous to EVs engineered with CD9. Intracellular cargo discharge from D4-EVs was successfully detected with the assistance of vesicular stomatitis virus glycoprotein. This study presents a novel strategy for recruiting POIs into EVs via a lipid-binding domain that ensures content release in recipient cells.

Data accessibility

The data that supports the findings of this study are available in the Supporting Information of this article. The source datasets generated for figures are available from the corresponding author ([email protected]) upon reasonable request.