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Aspirin-responsive gene switch regulating therapeutic protein expression

Author

Listed:
  • Jinbo Huang

    (ETH Zurich)

  • Ana Palma Teixeira

    (ETH Zurich)

  • Ting Gao

    (Westlake Laboratory of Life Sciences and Biomedicine)

  • Shuai Xue

    (ETH Zurich
    Westlake Laboratory of Life Sciences and Biomedicine)

  • Mingqi Xie

    (Westlake Laboratory of Life Sciences and Biomedicine
    Westlake University)

  • Martin Fussenegger

    (ETH Zurich
    University of Basel)

Abstract

Current small-molecule-regulated synthetic gene switches face clinical limitations such as cytotoxicity, long-term side-effects and metabolic disturbances. Here, we describe an advanced synthetic platform inducible by risk-free input medication (ASPIRIN), which is activated by acetylsalicylic acid (ASA/aspirin), a multifunctional drug with pain-relieving, anti-inflammatory, and cardiovascular benefits. To construct ASPIRIN, we repurpose plant salicylic acid receptors NPR1 and NPR4. Through domain truncations and high-throughput mutant library screening, we enhance their ASA sensitivity. Optimized NPR1 fused with a membrane-tethering myristoylation signal (Myr-NPR1) forms a complex with NPR4, which is fused with a DNA binding domain (VanR) and a transactivation domain (VP16). ASA induces dissociation of the Myr-NPR1/NPR4-VanR-VP16 complex, allowing nuclear translocation of NPR4-VanR-VP16 to activate VanR-operator-controlled gene expression. In male diabetic mice implanted with microencapsulated ASPIRIN-engineered cells, ASA regulates insulin expression, restores normoglycemia, alleviates pain and reduces biomarkers of diabetic neuropathy and inflammation. We envision this system will pave the way for aspirin-based combination gene therapies.

Suggested Citation

  • Jinbo Huang & Ana Palma Teixeira & Ting Gao & Shuai Xue & Mingqi Xie & Martin Fussenegger, 2025. "Aspirin-responsive gene switch regulating therapeutic protein expression," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57275-x
    DOI: 10.1038/s41467-025-57275-x
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    1. Shivesh Kumar & Raul Zavaliev & Qinglin Wu & Ye Zhou & Jie Cheng & Lucas Dillard & Jordan Powers & John Withers & Jinshi Zhao & Ziqiang Guan & Mario J. Borgnia & Alberto Bartesaghi & Xinnian Dong & Pe, 2022. "Structural basis of NPR1 in activating plant immunity," Nature, Nature, vol. 605(7910), pages 561-566, May.
    2. Zheng Qing Fu & Shunping Yan & Abdelaty Saleh & Wei Wang & James Ruble & Nodoka Oka & Rajinikanth Mohan & Steven H. Spoel & Yasuomi Tada & Ning Zheng & Xinnian Dong, 2012. "NPR3 and NPR4 are receptors for the immune signal salicylic acid in plants," Nature, Nature, vol. 486(7402), pages 228-232, June.
    3. Wei Wang & John Withers & Heng Li & Paul J. Zwack & Domnița-Valeria Rusnac & Hui Shi & Lijing Liu & Shunping Yan & Thomas R. Hinds & Mikelos Guttman & Xinnian Dong & Ning Zheng, 2020. "Structural basis of salicylic acid perception by Arabidopsis NPR proteins," Nature, Nature, vol. 586(7828), pages 311-316, October.
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