Chen Zhao-Peng, Zeng Wei-Jia, Lei Yan-Mei, Liang Wen-Bin, Yang Xia, Yuan Ruo, Yang Chaoyong, Zhuo Ying
Key Laboratory of Luminescence Analysis and Molecular Sensing (Southwest University), Ministry of Education, College of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, China.
Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, 400715, China.
Angew Chem Int Ed Engl. 2025 Jan 10;64(2):e202414064. doi: 10.1002/anie.202414064. Epub 2024 Nov 6.
Granzyme A (GzmA) secreted by natural killer (NK) cells has garnered considerable interest as a biomarker to evaluate the efficacy of cancer immunotherapy. However, current methodologies to selectively monitor the spatial distribution of GzmA in cancer cells during NK cell-targeted therapy are extremely challenging, primarily due to the existence of diverse cell populations, the low levels of GzmA expression, and the limited availability of GzmA probes. Herein we develop a multi-modular, structurally-ordered DNA nanodevice for evaluating NK cell-mediated cancer immunotherapy (MODERN), that permits spatioselective imaging of GzmA in cancer cells through GzmA-induced apurinic/apyrimidinic endonuclease 1 (APE1) inactivation. The MODERN incorporates multiple functional modules, including an APE1-gated recognition module, a photo-activated amplification module, an aptamer-mediated tumor-target module, and a polycatenane DNA module, enabling improved sensitivity and specificity towards intracellular GzmA. The MODERN was activated (on) in cancer cells due to the overexpression of APE1, whereas it remained silent (off) in the NK-treated cancer cells owing to the GzmA-induced APE1 inactivation. Furthermore, we demonstrated that GzmA-induced APE1 inactivation blocks the cellular repair of target cells, resulting in efficient cell death. This MODERN that relies on the specific inactivation of APE1 by GzmA should be beneficial for evaluating the efficacy of cancer immunotherapy.
自然杀伤（NK）细胞分泌的颗粒酶A（GzmA）作为评估癌症免疫治疗疗效的生物标志物已引起广泛关注。然而，目前在NK细胞靶向治疗过程中选择性监测癌细胞中GzmA空间分布的方法极具挑战性，主要原因是存在多种细胞群体、GzmA表达水平低以及GzmA探针的可用性有限。在此，我们开发了一种用于评估NK细胞介导的癌症免疫治疗的多模块、结构有序的DNA纳米装置（MODERN），它能够通过GzmA诱导的脱嘌呤/脱嘧啶内切酶1（APE1）失活对癌细胞中的GzmA进行时空选择性成像。MODERN包含多个功能模块，包括一个APE1门控识别模块、一个光激活放大模块、一个适体介导的肿瘤靶向模块和一个多链烷DNA模块，从而提高了对细胞内GzmA的敏感性和特异性。由于APE1的过表达，MODERN在癌细胞中被激活（开启），而由于GzmA诱导的APE1失活，它在经NK处理的癌细胞中保持沉默（关闭）。此外，我们证明GzmA诱导的APE1失活会阻断靶细胞的细胞修复，从而导致有效的细胞死亡。这种依赖于GzmA对APE1进行特异性失活的MODERN应该有助于评估癌症免疫治疗的疗效。
