On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system
Abstract Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58184-9 |
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| _version_ | 1849389868375867392 |
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| author | Yaqing Si Minghui He Yilin Li Jian Jiang Yuxuan Fan Shuai Xue Xinyuan Qiu Mingqi Xie |
| author_facet | Yaqing Si Minghui He Yilin Li Jian Jiang Yuxuan Fan Shuai Xue Xinyuan Qiu Mingqi Xie |
| author_sort | Yaqing Si |
| collection | DOAJ |
| description | Abstract Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into an engineered bipartite activator of calcium release–activated calcium (CRAC) channels, Ca2+ influx mediated by the STIM/Orai1 machinery was flexibly adjusted to depend on different user-defined input signals. Application of StimExo to various endocrine cells enables instant secretion of therapeutic hormones upon administration of safe and patient-compliant trigger compounds. StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true “sense-and-respond” cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest. |
| format | Article |
| id | doaj-art-56a4f7e47ee54c0282a9d559c6f1b89f |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-56a4f7e47ee54c0282a9d559c6f1b89f2025-08-20T03:41:50ZengNature PortfolioNature Communications2041-17232025-03-0116111410.1038/s41467-025-58184-9On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis systemYaqing Si0Minghui He1Yilin Li2Jian Jiang3Yuxuan Fan4Shuai Xue5Xinyuan Qiu6Mingqi Xie7School of Basic Medical Sciences, Fudan UniversitySchool of Basic Medical Sciences, Fudan UniversityWestlake Laboratory of Life Sciences and BiomedicineWestlake Laboratory of Life Sciences and BiomedicineWestlake Laboratory of Life Sciences and BiomedicineWestlake Laboratory of Life Sciences and BiomedicineDepartment of Biology and Chemistry, College of Science, National University of Defense TechnologyWestlake Laboratory of Life Sciences and BiomedicineAbstract Here, we present StimExo as a rational design strategy allowing various user-defined control signals to trigger calcium-dependent exocytosis and mediate on-demand protein secretion in cell-therapy settings. Using a modular framework incorporating inducible protein-protein interactions into an engineered bipartite activator of calcium release–activated calcium (CRAC) channels, Ca2+ influx mediated by the STIM/Orai1 machinery was flexibly adjusted to depend on different user-defined input signals. Application of StimExo to various endocrine cells enables instant secretion of therapeutic hormones upon administration of safe and patient-compliant trigger compounds. StimExo also mediated insulin exocytosis using a cell-based gene delivery strategy in vivo, accounting for real-time control of blood glucose homeostasis in male diabetic mice in response to the FDA-approved drug grazoprevir. This study achieves true “sense-and-respond” cell-based therapies and provides a platform for remote control of in vivo transgene activities using various trigger signals of interest.https://doi.org/10.1038/s41467-025-58184-9 |
| spellingShingle | Yaqing Si Minghui He Yilin Li Jian Jiang Yuxuan Fan Shuai Xue Xinyuan Qiu Mingqi Xie On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system Nature Communications |
| title | On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system |
| title_full | On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system |
| title_fullStr | On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system |
| title_full_unstemmed | On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system |
| title_short | On-demand treatment of metabolic diseases by a synthetic drug-inducible exocytosis system |
| title_sort | on demand treatment of metabolic diseases by a synthetic drug inducible exocytosis system |
| url | https://doi.org/10.1038/s41467-025-58184-9 |
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