Liu Yao, Lu Yiping, Ning Bo, Su Xiaomin, Yang Binru, Dong Haiqing, Yin Bo, Pang Zhiqing, Shen Shun
Key Laboratory of Spine and Spinal Cord Injury Repair, and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital. The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P. R. China.
Pharmacy Department & Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China.
ACS Nano. 2022 Mar 22;16(3):4102-4115. doi: 10.1021/acsnano.1c09818. Epub 2022 Mar 9.
The facultative intracellular bacterium () has great potential for development as a cancer vaccine platform given its properties. However, the clinical application of has been severely restricted due to its rapid clearance, compromised immune response in tumors, and inevitable side effects such as severe systemic inflammation after intravenous administration. Herein, an immunotherapy system was developed on the basis of natural red blood cell (RBC) membranes encapsulated with selective deletion of virulence factors (@RBC). The biomimetic @RBC not only generated a low systemic inflammatory response but also enhanced the accumulation in tumors due to the long blood circulation and tumor hypoxic microenvironment favoring anaerobic colonization. After genome screening of tumors treated with intravenous PBS, , or @RBC, it was first found that @RBC induced extensive pore-forming protein gasdermin C ()-dependent pyroptosis, which reversed immunosuppressive tumor microenvironment and promoted a systemic strong and durable anti-tumor immune response, resulting in an excellent therapeutic effect on solid tumors and tumor metastasis. Overall, @RBC, as an intravenous living bacterial therapy for the selective initiation of tumor pyrolysis, provided a proof-of-concept of live bacteria vaccine potentiating tumor immune therapy.
兼性胞内细菌（）因其特性在作为癌症疫苗平台开发方面具有巨大潜力。然而，由于其快速清除、肿瘤中免疫反应受损以及静脉注射后不可避免的副作用，如严重的全身炎症，其临床应用受到严重限制。在此，基于包裹有选择性缺失毒力因子的天然红细胞（RBC）膜开发了一种免疫治疗系统（@RBC）。仿生@RBC不仅产生低全身炎症反应，还由于长血液循环和有利于厌氧定植的肿瘤缺氧微环境而增强了在肿瘤中的积累。在用静脉注射PBS、或@RBC治疗的肿瘤进行基因组筛选后，首次发现@RBC诱导广泛的依赖孔形成蛋白gasdermin C（）的细胞焦亡，这逆转了免疫抑制性肿瘤微环境并促进了全身强烈且持久的抗肿瘤免疫反应，从而对实体瘤和肿瘤转移产生了优异的治疗效果。总体而言，@RBC作为一种用于选择性启动肿瘤热解的静脉内活菌疗法，为活菌疫苗增强肿瘤免疫治疗提供了概念验证。
