Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Institute of Molecular Medicine, Shanghai Key Laboratory of Nucleic Acid Chemistry and Nanomedicine, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Adv Sci (Weinh). 2024 Aug;11(32):e2400149. doi: 10.1002/advs.202400149. Epub 2024 Jun 19.
The activation of cyclic GMP-AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS-STING pathway activation, macrophage-selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer- or lipid-based delivery systems encounter difficulty in integrating multiple functions meanwhile maintaining precise control and simple procedures. Herein, inspired by cGAS being a natural DNA sensor, a modularized DNA nanodevice agonist (DNDA) is designed that enable macrophage-selective uptake and programmable activation of the cGAS-STING pathway through precise self-assembly. The resulting DNA nanodevice acts as both a nanocarrier and agonist. Upon local administration, it demonstrates the ability of macrophage-selective uptake, endosomal escape, and cytosolic release of the cGAS-recognizing DNA segment, leading to robust activation of the cGAS-STING pathway and enhanced antitumor efficacy. Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS-STING activation.
环鸟苷酸-腺苷酸（cGAMP）合酶（cGAS）及其衔接蛋白干扰素基因刺激物（STING）的激活被认为可以重新编程免疫抑制性肿瘤微环境，促进抗肿瘤免疫。为了提高 cGAS-STING 途径激活的效率，对于 STING 激动剂的递送来，巨噬细胞选择性摄取和可编程细胞质释放至关重要。然而，现有的聚合物或脂质基递送系统在整合多种功能的同时，难以精确控制和保持简单的程序。受 cGAS 作为天然 DNA 传感器的启发，本文设计了一种模块化 DNA 纳米器件激动剂（DNDA），通过精确的自组装实现了巨噬细胞选择性摄取和可编程激活 cGAS-STING 途径。所得 DNA 纳米器件既作为纳米载体又作为激动剂。局部给药后，它表现出对巨噬细胞选择性摄取、内体逃逸和细胞质中 cGAS 识别 DNA 片段释放的能力，从而强烈激活 cGAS-STING 途径并增强抗肿瘤功效。此外，DNDA 与免疫检查点阻断联合使用可产生协同治疗效果。该研究拓宽了 DNA 纳米技术作为 cGAS-STING 激活的免疫刺激物的应用。
