Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan 430072, China.
Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen 518132, China.
ACS Nano. 2024 May 14;18(19):12295-12310. doi: 10.1021/acsnano.4c01229. Epub 2024 May 2.
Immune checkpoint blockade (ICB) has brought tremendous clinical progress, but its therapeutic outcome can be limited due to insufficient activation of dendritic cells (DCs) and insufficient infiltration of cytotoxic T lymphocytes (CTLs). Evoking immunogenic cell death (ICD) is one promising strategy to promote DC maturation and elicit T-cell immunity, whereas low levels of ICD induction of solid tumors restrict durable antitumor efficacy. Herein, we report a genetically edited cell membrane-coated cascade nanozyme (gCM@MnAu) for enhanced cancer immunotherapy by inducing ICD and activating the stimulator of the interferon genes (STING) pathway. In the tumor microenvironment (TME), the gCM@MnAu initiates a cascade reaction and generates abundant cytotoxic hydroxyl (•OH), resulting in improved chemodynamic therapy (CDT) and boosted ICD activation. In addition, released Mn during the cascade reaction activates the STING pathway and further promotes the DC maturation. More importantly, activated immunogenicity in the TME significantly improves gCM-mediated PD-1/PD-L1 checkpoint blockade therapy by eliciting systemic antitumor responses. In breast cancer subcutaneous and lung metastasis models, the gCM@MnAu showed synergistically enhanced therapeutic effects and significantly prolonged the survival of mice. This work develops a genetically edited nanozyme-based therapeutic strategy to improve DC-mediated cross-priming of T cells against poorly immunogenic solid tumors.
免疫检查点阻断（ICB）带来了巨大的临床进展，但由于树突状细胞（DC）的激活不足和细胞毒性 T 淋巴细胞（CTL）的浸润不足，其治疗效果可能受到限制。引发免疫原性细胞死亡（ICD）是促进 DC 成熟和引发 T 细胞免疫的一种很有前途的策略，而实体瘤中 ICD 诱导水平低限制了持久的抗肿瘤疗效。在此，我们报告了一种基因编辑细胞膜包被级联纳米酶（gCM@MnAu），通过诱导 ICD 和激活干扰素基因刺激物（STING）途径增强癌症免疫治疗。在肿瘤微环境（TME）中，gCM@MnAu 引发级联反应并产生大量细胞毒性羟基（•OH），从而改善化学动力学治疗（CDT）并增强 ICD 激活。此外，级联反应过程中释放的 Mn 激活了 STING 途径，并进一步促进了 DC 的成熟。更重要的是，TME 中激活的免疫原性显著提高了 gCM 介导的 PD-1/PD-L1 检查点阻断治疗的效果，引发了全身性抗肿瘤反应。在乳腺癌皮下和肺转移模型中，gCM@MnAu 表现出协同增强的治疗效果，并显著延长了小鼠的存活时间。这项工作开发了一种基于基因编辑纳米酶的治疗策略，以改善 DC 介导的对免疫原性差的实体瘤的 T 细胞交叉引发。
