Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
ACS Appl Mater Interfaces. 2021 Oct 13;13(40):47407-47417. doi: 10.1021/acsami.1c16154. Epub 2021 Oct 1.
Pyroptosis is a programmed cell death to enhance immunogenicity of tumor cells, but pyroptosis-based immunotherapy is limited due to the immune escape involving myeloid-derived suppressor cells (MDSCs). Therefore, designing a nanoplatform to not only trigger apoptosis-pyroptosis transformation but also combat the MDSC-based immune escape is of great significance. As a proof-of-concept study, here, we designed a metal organic framework (MOF)-based nanoplatform to tailor the pyroptosis immunotherapy through disrupting the MDSC-mediated immunosuppression. By pH-responsive zeolitic imidazolate framework-8 (ZIF-8) modified with hyaluronic acid (HA), the chemotherapeutic drug mitoxantrone (MIT) and DNA demethylating agent hydralazine (HYD) were successfully co-encapsulated into ZIF-8 for achieving (M+H)@ZIF/HA nanoparticles. This nanoplatform demonstrated a powerful apoptosis-to-pyroptosis transformation with a potent disruption of MDSC-mediated T cell paralysis reducing immunosuppressive methylglyoxal by HYD. Overall, our two-pronged nanoplatform (M+H)@ZIF/HA can switch the cold tumor into an arsenal of antigens that stimulate robust immunological responses, while suppressing immune escape, collectively triggering vigorous cytotoxic T cell responses with remarkable tumor elimination and building a long-term immune memory response against metastasis.
细胞焦亡是一种增强肿瘤细胞免疫原性的程序性细胞死亡方式，但由于髓系来源抑制细胞（MDSC）的免疫逃逸，基于细胞焦亡的免疫疗法受到限制。因此，设计一种既能触发细胞凋亡-焦亡转化，又能对抗 MDSC 介导的免疫逃逸的纳米平台具有重要意义。作为概念验证研究，在这里，我们设计了一种基于金属有机骨架（MOF）的纳米平台，通过破坏 MDSC 介导的免疫抑制来定制细胞焦亡免疫疗法。通过 pH 响应的透明质酸（HA）修饰的沸石咪唑酯骨架-8（ZIF-8），成功地将化疗药物米托蒽醌（MIT）和 DNA 去甲基化剂肼（HYD）共包封到 ZIF-8 中，以实现（M+H）@ZIF/HA 纳米颗粒。该纳米平台具有强大的细胞凋亡-焦亡转化能力，能够有效破坏 MDSC 介导的 T 细胞麻痹，减少 HYD 产生的免疫抑制性甲基乙二醛。总之，我们的双管齐下的纳米平台（M+H）@ZIF/HA 可以将冷肿瘤转化为刺激强烈免疫反应的大量抗原，同时抑制免疫逃逸，共同引发强烈的细胞毒性 T 细胞反应，显著消除肿瘤并建立对转移的长期免疫记忆反应。
