State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University, Nanjing, 210023, China.
Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, China.
Angew Chem Int Ed Engl. 2023 Jun 12;62(24):e202303010. doi: 10.1002/anie.202303010. Epub 2023 May 3.
cGAS-STING-mediated DNA sensing is demonstrated to be critical for launching antitumor immunity. However, DNA-based cGAS-STING agonists are rarely reported owing to low cell permeability, poor biostability and, especially, limited length of exogenous DNA. Here, we present a virus-like particle which is self-assembled from long DNA building blocks generated through rolling-circle amplification (RCA) and covered with cationic liposomes. Based on long and densely packed DNA structure, it could efficiently induce liquid phase condensation of cGAS and activate STING signaling to produce inflammatory cytokines. Moreover, this virus-like particle could also trigger the formation of AIM2 inflammasome to induce gasdermin D-mediated pyroptosis, boosting antitumor immunity. Thus, this study provides a simple and robust strategy for cancer immunotherapy for clinical application. This is the first study to report the intrinsic immunogenicity of RCA products, thus facilitating their biomedical applications.
cGAS-STING 介导的 DNA 传感被证明对于启动抗肿瘤免疫至关重要。然而，由于细胞通透性低、生物稳定性差，尤其是外源 DNA 的长度有限，基于 DNA 的 cGAS-STING 激动剂很少被报道。在这里，我们展示了一种病毒样颗粒，它是由通过滚环扩增（RCA）产生的长 DNA 构建块自组装而成，并覆盖有阳离子脂质体。基于长而密集的 DNA 结构，它可以有效地诱导 cGAS 的液相凝聚，并激活 STING 信号转导以产生炎症细胞因子。此外，这种病毒样颗粒还可以触发 AIM2 炎性体的形成，诱导 gasdermin D 介导的细胞焦亡，从而增强抗肿瘤免疫。因此，本研究为临床应用提供了一种简单而强大的癌症免疫治疗策略。这是第一项报道 RCA 产物固有免疫原性的研究，从而促进了它们在生物医学中的应用。
