He Qingbin, Zheng Runxiao, Ma Junchi, Zhao Luyang, Shi Yafang, Qiu Jianfeng
School of Radiology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, 271000, China.
Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, China.
Biomater Res. 2023 Apr 15;27(1):29. doi: 10.1186/s40824-023-00374-x.
The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) signaling pathway has attracted great attention for its ability to up-regulate innate immune response and thus enhance cancer immunotherapy. However, many STING agonists limit the further advancement of immunotherapy due to weak tumor responsiveness or low activation efficiency. The responsive and effective activation of cGAS-STING signaling in tumors is a highly challenging process.
In this study, a manganese-based nanoplatform (MPCZ NPs) was constructed that could responsively and efficiently generate more manganese ions (Mn) and reactive oxygen species (ROS) to activate cGAS-STING signaling pathway. Briefly, manganese dioxide (MnO) was loaded with zinc protoporphyrin IX (ZPP) molecule and coated by polydopamine (PDA) embedded with NHHCO to obtain MPCZ NPs. Additionally, MPCZ NPs were evaluated in vitro and in vivo for their antitumor effects by methyl thiazolyl tetrazolium (MTT) assay and TUNEL assays, respectively.
In this system, tumor responsiveness was achieved by exogenous (laser irradiation) and endogenous (high levels GSH) stimulation, which triggered the collapse or degradation of PDA and MnO. Moreover, the release of Mn augmented the cGAS-STING signaling pathway and enhanced the conversion of hydrogen peroxide (HO) to hydroxyl radical (·OH) under NIR laser irradiation. Furthermore, the release of ZPP and the elimination of GSH by MPCZ NPs inhibited HO-1 activity and prevented ROS consumption, respectively.
This adopted open source and reduce expenditure strategy to effectively generate more ROS and Mn to responsively activate cGAS-STING signaling pathway, providing a new strategy for improving immunotherapy.
环磷酸鸟苷 - 磷酸腺苷合成酶 - 干扰素基因刺激因子（cGAS - STING）信号通路的激活因其上调先天免疫反应从而增强癌症免疫治疗的能力而备受关注。然而，许多STING激动剂由于肿瘤反应性弱或激活效率低，限制了免疫治疗的进一步发展。在肿瘤中响应性且有效地激活cGAS - STING信号是一个极具挑战性的过程。
在本研究中，构建了一种基于锰的纳米平台（MPCZ NPs），其能够响应并有效地产生更多的锰离子（Mn）和活性氧（ROS）以激活cGAS - STING信号通路。简而言之，将二氧化锰（MnO）负载锌原卟啉IX（ZPP）分子，并用嵌入NHHCO的聚多巴胺（PDA）包被以获得MPCZ NPs。此外，分别通过甲基噻唑基四氮唑（MTT）法和TUNEL法在体外和体内评估MPCZ NPs的抗肿瘤作用。
在该系统中，通过外源性（激光照射）和内源性（高水平谷胱甘肽）刺激实现肿瘤反应性，这触发了PDA和MnO的崩塌或降解。此外，Mn的释放增强了cGAS - STING信号通路，并在近红外激光照射下增强了过氧化氢（HO）向羟基自由基（·OH）的转化。此外，MPCZ NPs释放的ZPP和对谷胱甘肽的清除分别抑制了HO - 1活性并防止了ROS的消耗。
这种采用开源和降低成本的策略有效地产生更多的ROS和Mn以响应性地激活cGAS - STING信号通路，为改善免疫治疗提供了一种新策略。
