Zhao Mei-Ling, Lei Yan-Mei, Tang Jing-Yi, Li Wen, Cao Xin-Yu, Liang Wen-Bin, Yuan Ruo, Yang Chaoyong, Zhuo Ying
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, Institute of Developmental Biology and Regenerative Medicine, College of Chemistry and Chemical Engineering, Southwest University Chongqing 400715 P. R. China
Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University Shanghai 2002127 P. R. China.
Chem Sci. 2024 Dec 23;16(4):1783-1790. doi: 10.1039/d4sc06493c. eCollection 2025 Jan 22.
Utilizing the cGAS-STING pathway to combat immune evasion is one of the most promising strategies for enhancing cancer immunotherapy. However, current techniques for activating the cGAS-STING pathway often face a dilemma, mainly due to the balance between efficacy and safety. Here, we develop a uracil base lesion-gated dumbbell DNA nanodevice (UBLE) that allows on-demand activation and termination of the cGAS-STING pathway in tumor cells, thereby enhancing cancer immunotherapy. The UBLE integrates two deoxyuridines (dU) in the stem for DNA lesion recognition, two locked complementary primer sequences (primers A and B) for DNA self-assembly, and a Förster resonance energy transfer pair (Cy3 and Cy5) attached to the loop for activation assessment. Upon the orthogonal recognition of tumor-specific repair indicators (UDG and APE1), the UBLE undergoes a conformational change to create massive nicked double-stranded DNA (dsDNA) units. These units self-assemble to generate long fluorescent dsDNA structures, permitting selective evaluation and on-demand activation of the cGAS-STING pathway. Furthermore, we demonstrate that the UBLE can effectively activate the cGAS-STING pathway in tumor cells, enhancing NK cell-targeted cancer immunotherapy. This work develops a DNA lesion-gated strategy for on-demand activation and termination of the cGAS-STING pathway, affording an innovative avenue for enhancing cancer immunotherapy.
利用cGAS-STING通路对抗免疫逃逸是增强癌症免疫治疗最有前景的策略之一。然而，目前激活cGAS-STING通路的技术常常面临两难境地，主要是由于疗效和安全性之间的平衡。在此，我们开发了一种尿嘧啶碱基损伤门控哑铃状DNA纳米装置（UBLE），它能够在肿瘤细胞中按需激活和终止cGAS-STING通路，从而增强癌症免疫治疗。UBLE在茎干中整合了两个脱氧尿苷（dU）用于DNA损伤识别，两个锁定的互补引物序列（引物A和引物B）用于DNA自组装，以及一对附着在环上的Förster共振能量转移对（Cy3和Cy5）用于激活评估。在对肿瘤特异性修复指标（UDG和APE1）进行正交识别后，UBLE发生构象变化，产生大量带切口的双链DNA（dsDNA）单元。这些单元自组装形成长荧光dsDNA结构，允许对cGAS-STING通路进行选择性评估和按需激活。此外，我们证明UBLE能够在肿瘤细胞中有效激活cGAS-STING通路，增强以NK细胞为靶点的癌症免疫治疗。这项工作开发了一种用于按需激活和终止cGAS-STING通路的DNA损伤门控策略，为增强癌症免疫治疗提供了一条创新途径。
