Although engineered T cells with transgenic chimeric antigen receptors (CARs) have made a breakthrough in cancer therapeutics, this approach still faces many challenges in the specificity, efficacy, and self-safety of genetic engineering. Here, we developed a nano-biohybrid DNA engager-reprogrammed T-cell receptor (EN-TCR) system to improve the specificity and efficacy, mitigate the excessive activation, and shield against risks from transgenesis, thus achieving a diversiform and precise control of the T-cell response. Utilizing modular assembly, the EN-TCR system can graft different specificities on T cells via antibody assembly. Besides, the designability of DNA hybridization enables precise target recognition by the library of multiantigen cell recognition circuits and allows gradual tuning of the T-cell activation level by the signaling switch and independent control over different types of T cells. Furthermore, we demonstrated the effectiveness of the system in tumor models. Together, this study provides a nongenetic T-cell engineering strategy to overcome major hindrances in T-cell therapy and may be extended to a general and convenient cell engineering strategy.

中文翻译：

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重新编程 T 细胞受体的纳米生物杂交 DNA 接合器

尽管具有转基因嵌合抗原受体 (CAR) 的工程化 T 细胞在癌症治疗方面取得了突破，但这种方法在基因工程的特异性、有效性和自身安全性方面仍面临许多挑战。在这里，我们开发了一种纳米生物杂交 DNA 接合器重编程 T 细胞受体 (EN-TCR) 系统，以提高特异性和有效性，减轻过度激活，并屏蔽转基因风险，从而实现对 T 细胞的多样化和精确控制。 T 细胞反应。利用模块化组装，EN-TCR 系统可以通过抗体组装将不同的特异性移植到 T 细胞上。除了，DNA 杂交的可设计性使多抗原细胞识别电路库能够精确识别目标，并允许通过信号开关逐步调节 T 细胞激活水平，并独立控制不同类型的 T 细胞。此外，我们证明了该系统在肿瘤模型中的有效性。总之，这项研究提供了一种非遗传性 T 细胞工程策略，以克服 T 细胞治疗中的主要障碍，并可能扩展为一种通用且方便的细胞工程策略。