Regulation of therapeutic protein release in response to circadian biomarkers

Nik Franko, Shichao Li, Silvia Galvan, Zsoka Csorba, Ana Palma Teixeira, Mingqi Xie and Martin Fussenegger ()
Additional contact information
Nik Franko: ETH Zurich
Shichao Li: Westlake Laboratory of Life Sciences and Biomedicine
Silvia Galvan: ETH Zurich
Zsoka Csorba: ETH Zurich
Ana Palma Teixeira: ETH Zurich
Mingqi Xie: Westlake Laboratory of Life Sciences and Biomedicine
Martin Fussenegger: ETH Zurich

Nature Communications, 2025, vol. 16, issue 1, 1-9

Abstract: Abstract The human circadian clock integrates external environmental changes and internal physiological signals to generate natural oscillations of secreted endocrine signals to regulate diverse biological processes. Here, we explore human receptors responsive to molecules displaying in vivo oscillatory patterns and identify melatonin receptor 1A (MTNR1A) as a promising molecular sensor to trigger transgene expression. We engineer a melatonin-inducible gene switch consisting of ectopically expressed MTNR1A linked to an amplifier module utilizing the native Gαs protein-mediated cell signaling cascade, which involves adenylyl cyclase, cAMP, protein kinase A and the cAMP-responsive transcription factor CREB, to drive transgene expression from a synthetic promoter. This system operates within the physiological melatonin concentration range, selectively responding to night-phase levels of the diurnal rhythm, while remaining unresponsive to day-phase levels. Such temporal control suggests its potential for personalized cell- and gene-based therapies requiring once-per-day dosing regimen. As proof-of-concept, we show that alginate-encapsulated engineered cells implanted in C3H/HeJ male mice can translate circadian inputs or clinically licensed MTNR1A agonists into regulated GLP-1 expression as a therapeutic output exclusively secreted during nighttime, highlighting potential as an experimental cell therapy for obesity-dependent type-2 diabetes.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-64761-9 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64761-9

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-64761-9

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().