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

  • Nat Commun. 2025 Jul 17;16(1):6587. doi: 10.1038/s41467-025-61877-w.
Ni Zhen  #  1  2 ,  Yue Yan  #  3  4 ,  Guangya Zhu  #  5 ,  Tianxin Zhu  2 ,  Qi Zhang  1  2 ,  Qi Chen  2 ,  Yan Guo  2 ,  Jidong Zhu  6  7 ,  Qiuhui Pan  8  9  10  11 ,  Jingjing Xie  12
Affiliations
  • 1. Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 2. Lingang Laboratory, Shanghai, 200031, China.
  • 3. School of Physical Science and Technology & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, 201210, China.
  • 4. Etern Biopharma, 1505 Zuchongzhi Road, Shanghai, 201203, China.
  • 5. Lingang Laboratory, Shanghai, 200031, China. [email protected].
  • 6. Etern Biopharma, 1505 Zuchongzhi Road, Shanghai, 201203, China. [email protected].
  • 7. Tianjin Medical University, 22 Qixiangtai Road, Tianjin, 300070, China. [email protected].
  • 8. Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. [email protected].
  • 9. Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. [email protected].
  • 10. Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics, Shanghai, 200127, China. [email protected].
  • 11. Sanya Women and Children's Hospital Managed by Shanghai Children's Medical Center, Sanya, 572000, China. [email protected].
  • 12. School of Physical Science and Technology & State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • # Contributed equally.
PMID: 40675979 DOI: 10.1038/s41467-025-61877-w
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.

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