A mediator-free sonogenetic switch for therapeutic protein expression in mammalian cells.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0411011 Publication Model: Print Cited Medium: Internet ISSN: 1362-4962 (Electronic) Linking ISSN: 03051048 NLM ISO Abbreviation: Nucleic Acids Res Subsets: MEDLINE

Publication: 1992- : Oxford : Oxford University Press
Original Publication: London, Information Retrieval ltd.

Gene Expression Regulation*/radiation effects ; Ultrasonic Waves*; Animals ; Kelch-Like ECH-Associated Protein 1/genetics ; Kelch-Like ECH-Associated Protein 1/metabolism ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Humans ; Mice ; Reactive Oxygen Species/metabolism ; Antioxidant Response Elements/genetics ; Diabetes Mellitus, Type 1/therapy ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism

An ultrasound-responsive transgene circuit can provide non-invasive, spatiotemporally precise remote control of gene expression and cellular behavior in synthetic biology applications. However, current ultrasound-based systems often rely on nanoparticles or harness ultrasound's thermal effects, posing risks of tissue damage and cellular stress that limit their therapeutic potential. Here, we present Spatiotemporal Ultrasound-induced Protein Expression Regulator (SUPER), a novel gene switch enabling mediator-free, non-invasive and direct regulation of protein expression via ultrasound in mammalian cells. SUPER leverages the mammalian reactive oxygen species (ROS) sensing system, featuring KEAP1 (Kelch-like ECH-associated protein 1), NRF2 (nuclear factor erythroid 2-related factor 2), and antioxidant response element (ARE) as its core components. We demonstrate that low-intensity (1.5 W/cm2, ∼45 kHz), brief (40 s) ultrasound exposure generates non-toxic levels of ROS, activating the KEAP1/NRF2 pathway in engineered cells and leading to the controlled expression of target gene(s) via a synthetic ARE promoter. The system exhibits robust expression dynamics, excellent reversibility, and functionality in various cell types, including human mesenchymal stem cell-derived lines (hMSC-TERT). In a proof-of-concept study, ultrasound stimulation of subcutaneously implanted microencapsulated engineered cells stably expressing the sonogenetic circuit in a type 1 diabetic mouse model triggered sufficient insulin production to restore normoglycemia. Our work highlights ultrasound's potential as a precise and non-invasive tool for advancing cell and gene therapies in personalized medicine.
(© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

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785800 International ERC_ European Research Council; Switzerland SNSF_ Swiss National Science Foundation; ETH Zurich

0 (Kelch-Like ECH-Associated Protein 1)
0 (NF-E2-Related Factor 2)
0 (Reactive Oxygen Species)
0 (KEAP1 protein, human)
0 (NFE2L2 protein, human)

Date Created: 20250321 Date Completed: 20250514 Latest Revision: 20250514

20250514

PMC11925730

10.1093/nar/gkaf191

40114374