School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering (Ministry of Education), Frontiers Science Center for Synthetic Biology (Ministry of Education), Tianjin University, Tianjin 300350, P. R. China.
Tianjin Key Laboratory of Ion and Molecular Function in Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 3000211, P. R. China.
ACS Nano. 2024 Aug 20;18(33):21855-21872. doi: 10.1021/acsnano.3c12375. Epub 2024 Aug 7.
Malignant pleural effusions (MPEs) are hard to treat, and their onset usually signals terminal cancer. Immunotherapies hold promise but must overcome the immunosuppressive MPE microenvironment. Herein, we treat MPEs synergistically combining two emerging cancer therapy modalities: enzyme-dynamic therapy (EDT) and metalloimmunotherapy. To do so, a nanoplatform termed "A-R-SOME" was developed which comprises MPE-targeted M1 type extracellular vesicles (EVs) loaded with (1) a manganese-based superoxide dismutase (SOD) enzyme, (2) stimulator of interferon genes (STING) agonist diABZI-2, and (3) signal transducer and an activator of transcription 3 (STAT3) small interfering RNA. Endogenous reactive oxygen species within tumors induced immunogenic cell death by EDT, along with STING activation by both Mn and diABZI-2, and suppression of the STAT3 pathway. Systemically administered A-R-SOME alleviated the MPE immunosuppressive microenvironment, triggered antitumor systemic immunity, and long-term immune memory, leading to the complete eradication of MPE and pleural tumors with 100% survival rate in an aggressive murine model. A-R-SOME-induced immune effects were also observed in human patient-derived MPE, pointing toward the translation potential of A-R-SOME as an experimental malignancy treatment.
恶性胸腔积液（MPE）难以治疗，其发作通常预示着癌症晚期。免疫疗法前景广阔，但必须克服免疫抑制的 MPE 微环境。在此，我们通过联合两种新兴的癌症治疗模式来协同治疗 MPE：酶动态治疗（EDT）和金属免疫疗法。为此，开发了一种名为“ A-R-SOME”的纳米平台，该平台包含针对 MPE 的 M1 型细胞外囊泡（EV），负载有：（1）基于锰的超氧化物歧化酶（SOD）酶；（2）干扰素基因刺激物（STING）激动剂 diABZI-2；（3）信号转导子和转录激活子 3（STAT3）小干扰 RNA。EDT 通过肿瘤内的内源性活性氧物质诱导免疫原性细胞死亡，同时 Mn 和 diABZI-2 激活 STING，并抑制 STAT3 通路。全身给予 A-R-SOME 缓解了 MPE 的免疫抑制微环境，触发了抗肿瘤的全身免疫和长期免疫记忆，导致在侵袭性小鼠模型中完全消除 MPE 和胸膜肿瘤，生存率达到 100%。在源自人类患者的 MPE 中也观察到了 A-R-SOME 诱导的免疫效应，表明 A-R-SOME 作为一种实验性恶性肿瘤治疗具有转化潜力。
