Programmable Synthetic Protein Circuits for the Identification and Suppression of Hepatocellular Carcinoma
Programmable Synthetic Protein Circuits for the Identification and Suppression of Hepatocellular Carcinoma
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DOI：
10.1016/j.omto.2020.03.008
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发表时间：
2020-06-26
影响因子：
5.7
通讯作者：
Gao, Yi
中科院分区：
文献类型：
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作者：
Han, Xu;Yang, Jiong;Gao, Yi
精确识别和杀死肿瘤细胞是肿瘤治疗的不懈追求。合成基因电路已经成为解决这些问题的智能武器。基于转录后调控的基因电路能够比基于转录调控的系统更快地响应，后者需要转录和翻译，显示出上级安全性。本研究构建了具有两个控制层的无合成启动子的基因电路，以提高对肿瘤细胞的特异性识别。使用分裂TEV，我们设计并验证了蛋白质相互作用（PPI）传感的基本控制层。建立另一个正交控制层以感测特定蛋白质。两层被集成以产生感测PPI和特定蛋白质的基因电路，形成10个逻辑门。为了证明该系统的实用性，该电路被设计成感测甲胎蛋白（AFP）表达和雅普和14-3-3 sigma之间的PPI，肝细胞癌（HCC）的匹配谱。基因电路负载的细胞区分HCC与其他细胞，并释放治疗性抗体，表现出体外和体内治疗效果。
Precisely identifying and killing tumor cells are diligent pursuits in oncotherapy. Synthesized gene circuits have emerged as an intelligent weapon to solve these problems. Gene circuits based on post-transcriptional regulation enable a faster response than systems based on transcriptional regulation, which requires transcription and translation, showing superior safety. In this study, synthetic-promoter-free gene circuits possessing two control layers were constructed to improve the specific recognition of tumor cells. Using split-TEV, we designed and verified the basic control layer of protein-protein interaction (PPI) sensing. Another orthogonal control layer was built to sense specific proteins. Two layers were integrated to generate gene circuits sensing both PPI and specific proteins, forming 10 logic gates. To demonstrate the utility of this system, the circuit was engineered to sense alpha-fetoprotein (AFP) expression and the PPI between YAP and 14-3-3 sigma, the matching profile of hepatocellular carcinoma (HCC). Gene-circuit-loaded cells distinguished HCC from other cells and released therapeutic antibodies, exhibiting in vitro and in vivo therapeutic effects.