Localized Degradation of Neutrophil Extracellular Traps by Photoregulated Enzyme Delivery for Cancer Immunotherapy and Metastasis Suppression
Localized Degradation of Neutrophil Extracellular Traps by Photoregulated Enzyme Delivery for Cancer Immunotherapy and Metastasis Suppression
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通过光调节酶递送局部降解中性粒细胞胞外陷阱用于癌症免疫治疗和转移抑制
DOI：
10.1021/acsnano.1c09318
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发表时间：
2022-02-22
期刊：
影响因子：
17.1
通讯作者：
Duan, Hongwei
中科院分区：
文献类型：
--
作者：
Chen, Jiayuan;Hou, Shuai;Duan, Hongwei
中性粒细胞胞外陷阱（NET）的挤出是宿主针对病原体的一种基本先天免疫防御，最近被认为与癌症对免疫疗法的抵抗和远处转移有关。这些发现突出了癌症引起的炎症的有趣领域和潜在的治疗策略。事实证明，用 DNase I 破坏现有的 NET 可以增强肿瘤免疫疗法的疗效并减弱转移扩散。然而，DNase I 的全身生物分布引发了安全问题，可能会损害宿主对感染的防御能力。因此，肿瘤特异性递送和转移性生态位靶向效应是 NET 局部降解的有吸引力的选择。我们设计了一个具有广谱光活性的等离子体金黑体（AuPB）核心和介孔聚多巴胺（mPDA）外壳的纳米平台，可有效加载和光调控释放DNase I。第二次近红外（NIR-II）光照射触发的按需释放的DNase I打破了“NET介导的物理屏障”，从而增加了活体小鼠中免疫细胞毒性细胞与肿瘤细胞的接触，并使免疫检查点治疗敏感。原发性结直肠癌（CRC）。此外，系统递送的 AuPB@mPDA 载体在肝脏（CRC 转移最常见的部位）中的沉积和光控货物释放消除了 NET 介导的循环肿瘤细胞捕获，从而消除了转移播种。我们的研究结果表明，NIR-II 窗口中光活性载体对 DNase I 的局部光调节释放代表了免疫介导的肿瘤消退和转移抑制的翻译途径。
Extrusion of neutrophil extracellular traps (NETs), a fundamental host innate immune defense against pathogens, has recently been linked to cancer resistance to immunotherapy and distant metastasis. These findings highlight interesting areas of cancer-elicited inflammation and potential therapeutic strategies. Disrupting existing NETs with DNase I has been proved to enhance the therapeutic efficacy of tumor immunotherapy and attenuate metastatic spread. However, systemic biodistribution of DNase I raises safety issues, potentially impairing host defense against infection. Hence, tumor-specific delivery and metastatic niche-targeted effects are attractive options for localized degradation of NETs. We have engineered a nanoplatform with a plasmonic gold blackbody (AuPB) core with broad-spectrum photo activity and a mesoporous polydopamine (mPDA) shell for efficient loading and photoregulated release of DNase I. The on-demand released DNase I triggered by the second near-infrared (NIR-II) light irradiation breaks the "NET-mediated physical barrier", thereby increasing the contact of immune cytotoxic cells with tumor cells in living mice and sensitizing immune checkpoint therapy of primary colorectal cancer (CRC). Moreover, the deposition and light-controlled cargo release from systemically delivered AuPB@mPDA carriers in liver, the most frequent site of CRC metastasis, abolished NET-mediated capture of circulating tumor cells and hence metastatic seeding. Our findings indicate that the localized, light-regulated release of DNase I by photoactive carriers in the NIR-II window represent a translational route for immune-mediated tumor regression and metastasis inhibition.