Nitroglycerin-responsive gene switch for the on-demand production of therapeutic proteins

IF 26.8 1区医学 Q1 ENGINEERING, BIOMEDICAL

Nature Biomedical Engineering Pub Date : 2025-02-14 DOI:10.1038/s41551-025-01350-7

Mohamed Mahameed, Shuai Xue, Benjamin Danuser, Ghislaine Charpin-El Hamri, Mingqi Xie, Martin Fussenegger

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Abstract

Gene therapies and cell therapies require precise, reversible and patient-friendly control over the production of therapeutic proteins. Here we present a fully human nitric-oxide-responsive gene-regulation system for the on-demand and localized release of therapeutic proteins through clinically licensed nitroglycerin patches. Designed for simplicity and robust human compatibility, the system incorporates human mitochondrial aldehyde dehydrogenase for converting nitroglycerin into nitric oxide, which then activates soluble guanylate cyclase to produce cyclic guanosine monophosphate, followed by protein kinase G to amplify the signal and to trigger target gene expression. In a proof-of-concept study, human cells expressing the nitroglycerin-responsive system were encapsulated and implanted subcutaneously in obese mice with type 2 diabetes. Transdermal nitroglycerin patches applied over the implant enabled the controlled and reversible production of glucagon-like peptide-1 throughout the 35-day experimental period, effectively restoring blood glucose levels in these mice without affecting heart rate or blood pressure. The approach may facilitate the development of safe, convenient and responsive implantable devices for the sustained delivery of biopharmaceuticals for the management of chronic diseases.

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硝化甘油反应基因开关，用于按需生产治疗蛋白

基因治疗和细胞治疗需要对治疗蛋白的产生进行精确、可逆和对患者友好的控制。在这里，我们提出了一个完全的人类一氧化氮应答基因调控系统，用于通过临床许可的硝酸甘油贴片按需和局部释放治疗性蛋白质。该系统设计简单，具有强大的人体相容性，包含人线粒体醛脱氢酶，用于将硝酸甘油转化为一氧化氮，然后激活可溶性鸟苷酸环化酶产生环鸟苷单磷酸，随后是蛋白激酶G来放大信号并触发目标基因表达。在一项概念验证研究中，表达硝酸甘油反应系统的人类细胞被包裹并植入患有2型糖尿病的肥胖小鼠皮下。在35天的实验期间，植入物上的透皮硝酸甘油贴片能够控制和可逆地产生胰高血糖素样肽-1，在不影响心率或血压的情况下有效地恢复这些小鼠的血糖水平。该方法可能有助于开发安全、方便和反应灵敏的可植入装置，用于持续输送用于慢性疾病管理的生物制药。

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来源期刊

Nature Biomedical Engineering Medicine-Medicine (miscellaneous)

CiteScore

45.30

自引率

1.10%

发文量

138

期刊介绍： Nature Biomedical Engineering is an online-only monthly journal that was launched in January 2017. It aims to publish original research, reviews, and commentary focusing on applied biomedicine and health technology. The journal targets a diverse audience, including life scientists who are involved in developing experimental or computational systems and methods to enhance our understanding of human physiology. It also covers biomedical researchers and engineers who are engaged in designing or optimizing therapies, assays, devices, or procedures for diagnosing or treating diseases. Additionally, clinicians, who make use of research outputs to evaluate patient health or administer therapy in various clinical settings and healthcare contexts, are also part of the target audience.