Engineering bi-directional chemically-modulated synthetic condensates for cellular control

Ni Zhen, Yue Yan, Guangya Zhu (), Tianxin Zhu, Qi Zhang, Qi Chen, Yan Guo, Jidong Zhu (), Qiuhui Pan () and Jingjing Xie ()
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Ni Zhen: Shanghai Jiao Tong University School of Medicine
Yue Yan: ShanghaiTech University
Guangya Zhu: Lingang Laboratory
Tianxin Zhu: Lingang Laboratory
Qi Zhang: Shanghai Jiao Tong University School of Medicine
Qi Chen: Lingang Laboratory
Yan Guo: Lingang Laboratory
Jidong Zhu: Etern Biopharma
Qiuhui Pan: Shanghai Jiao Tong University School of Medicine
Jingjing Xie: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Biomolecular condensates are membraneless compartments involved in a wide range of cellular processes. Despite their fundamental role in the spatiotemporal regulation of cellular functions, tools for precisely manipulating phase-separated condensates remain limited, and effective methods for discovering and functionalizing tunable phase separation modules from natural proteins are lacking. Here we present a rational engineering approach for androgen receptor (AR) and its clinically used drugs to create a chemical genetic platform, ARDrop, enabling condensates formation and dissolution. This platform is applied to a diverse set of proteins to achieve intended cellular functions, ensuring robust and long-lasting functionality through stable liquid-like properties. Our work develops a powerful toolkit for reversible manipulation of condensates that can be used for dissection of complicated cell signaling, laying the foundation for engineering designer condensates for synthetic biology applications.

Date: 2025
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DOI: 10.1038/s41467-025-61877-w

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