Hou Lin, Tian Chunyu, Yan Yingshan, Zhang Lewen, Zhang Huijuan, Zhang Zhenzhong
School of Pharmaceutical Sciences, Zhengzhou University, and Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Zhengzhou University, Zhengzhou 450001, China.
ACS Nano. 2020 Apr 28;14(4):3927-3940. doi: 10.1021/acsnano.9b06111. Epub 2020 Apr 20.
Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are essential components of the innate immune sensors to cytosolic DNA and elicit type I interferon (IFN). Recent studies have revealed that manganese (Mn) can enhance cGAS and STING activation to viral infection. However, the role of Mn in antitumor immunity has not been explored. Here, we designed a nanoactivator, which can induce the presence of DNA in cytoplasm and simultaneously elevate Mn accumulation within tumor cells. In detail, amorphous porous manganese phosphate (APMP) NPs that are highly responsive to tumor microenvironment were employed to construct doxorubicin (DOX)-loaded and phospholipid (PL)-coated hybrid nanoparticles (PL/APMP-DOX NPs). PL/APMP-DOX NPs were stably maintained during systemic circulation, but triggered to release DOX for inducing DNA damage and Mn to augment cGAS/STING activity. We found that PL/APMP-DOX NPs with superior tumor-targeting capacity boosted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. Furthermore, the NPs increased production of type I IFN and secretion of pro-inflammatory cytokines (for example, TNF-α and IL-6). Consequently, PL/APMP-DOX NPs exhibited excellent antitumor efficacy and prolonged the lifespan of the tumor-bearing mice. Collectively, we developed a PL-decorated Mn-based hybrid nanoactivator to intensify immune activation and that might provide therapeutic potential for caner immunotherapy.
环磷酸鸟苷-腺苷合成酶（cGAS）和干扰素基因刺激因子（STING）是胞质DNA固有免疫传感器的重要组成部分，并能引发I型干扰素（IFN）。最近的研究表明，锰（Mn）可以增强cGAS和STING对病毒感染的激活作用。然而，Mn在抗肿瘤免疫中的作用尚未得到探索。在此，我们设计了一种纳米激活剂，它可以诱导细胞质中DNA的存在，同时提高肿瘤细胞内Mn的积累。具体而言，利用对肿瘤微环境高度敏感的无定形多孔磷酸锰（APMP）纳米颗粒构建负载阿霉素（DOX）并包裹磷脂（PL）的混合纳米颗粒（PL/APMP-DOX NPs）。PL/APMP-DOX NPs在体循环过程中稳定存在，但会触发释放DOX以诱导DNA损伤，并释放Mn以增强cGAS/STING活性。我们发现，具有优异肿瘤靶向能力的PL/APMP-DOX NPs可促进树突状细胞成熟，增加细胞毒性T淋巴细胞浸润以及自然杀伤细胞向肿瘤部位的募集。此外，这些纳米颗粒增加了I型IFN的产生和促炎细胞因子（例如TNF-α和IL-6）的分泌。因此，PL/APMP-DOX NPs表现出优异的抗肿瘤疗效，并延长了荷瘤小鼠的寿命。总体而言，我们开发了一种PL修饰的基于Mn的混合纳米激活剂以增强免疫激活，这可能为癌症免疫治疗提供治疗潜力。
