Aspirin-responsive gene switch regulating therapeutic protein expression

Jinbo Huang, Ana Palma Teixeira, Ting Gao, Shuai Xue, Mingqi Xie and Martin Fussenegger ()
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Jinbo Huang: ETH Zurich
Ana Palma Teixeira: ETH Zurich
Ting Gao: Westlake Laboratory of Life Sciences and Biomedicine
Shuai Xue: ETH Zurich
Mingqi Xie: Westlake Laboratory of Life Sciences and Biomedicine
Martin Fussenegger: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57275-x

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