Metal–Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells

作者：Yang Liu, Rui Niu, Xiaodong Zhang, Bin Zhang, Xiaokai Chen, Jingjing Guo, Shuyan Song, Yinghui Wang, Hongjie Zhang, Yanli Zhao · 发表于：ACS Nano · 年份：2024 · DOI：10.1021/acsnano.4c01518 · 被引用次数：56 · 研究领域：Nanoplatforms for cancer theranostics、Phagocytosis and Immune Regulation、Heme Oxygenase-1 and Carbon Monoxide

Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal–organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells’ membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating • O 2 –, and the Cu-THBQ/AX catalyzes O 2 and H 2 O 2 to • O 2 – and • OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of • OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from “cold” to “hot” conditions, making it an effective antigen pool. Thi...