Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity
Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity
复制标题
DOI：
10.1021/acsnano.9b06111
复制
发表时间：
2020-04-28
期刊：
影响因子：
17.1
通讯作者：
Zhang, Zhenzhong
中科院分区：
文献类型：
--
作者：
Hou, Lin;Tian, Chunyu;Zhang, Zhenzhong
环状GMP-AMP合成酶(CGAS)和干扰素基因刺激物(STING)是针对胞浆DNA的天然免疫感受器的重要组成部分，可诱生I型干扰素。最近的研究表明，锰可以增强cGAS和刺激物对病毒感染的激活作用。然而，锰在抗肿瘤免疫中的作用尚不清楚。在这里，我们设计了一种纳米激活剂，它可以诱导DNA在细胞质中的存在，同时提高肿瘤细胞内Mn2+的积累。利用对肿瘤微环境具有高度响应性的无定形多孔磷酸锰纳米粒构建阿霉素(DOX)负载磷脂(PL)杂化纳米粒(PL/APMP-DOX NPs)。PL/APMP-DOX纳米粒在体循环中保持稳定，但被触发释放DOX以诱导DNA损伤和Mn2+增强cGAS/STIN活性。我们发现，具有良好肿瘤靶向能力的PL/APMP-DOX纳米粒促进了树突状细胞的成熟，增加了细胞毒性T淋巴细胞的渗透，并促进了自然杀伤细胞向肿瘤部位的募集。此外，NPs增加了I型干扰素的产生和促炎细胞因子的分泌(例如，TNF-α和IL-6)。因此，PL/APMP-DOX纳米粒具有良好的抗肿瘤效果，并延长了荷瘤小鼠的寿命。总之，我们开发了一种PL修饰的锰基杂化纳米激活剂，以增强免疫激活，并可能为肿瘤免疫治疗提供治疗潜力。
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 Mn2+ 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 Mn2+ 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-alpha 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.