A plug-and-play monofunctional platform for targeted degradation of extracellular proteins and vesicles

Shasha Yao, Yi Wang, Qian Tang, Yujie Yin, Yu Geng, Lei Xu, Shifu Liang, Jiajia Xiang (), Jiaqi Fan, Jianbin Tang, Jian Liu (), Shiqun Shao () and Youqing Shen
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Shasha Yao: Zhejiang University
Yi Wang: Zhejiang University
Qian Tang: Zhejiang University
Yujie Yin: Zhejiang University
Yu Geng: The Fourth Affiliated Hospital Zhejiang University School of Medicine
Lei Xu: The Fourth Affiliated Hospital Zhejiang University School of Medicine
Shifu Liang: Zhejiang University
Jiajia Xiang: Zhejiang University
Jiaqi Fan: Zhejiang University
Jianbin Tang: Zhejiang University
Jian Liu: Zhejiang University
Shiqun Shao: Zhejiang University
Youqing Shen: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.

Date: 2024
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DOI: 10.1038/s41467-024-51720-z

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