Cellular membrane-based vesicles displaying a reconstructed B cell maturation antigen for multiple myeloma therapy by dual targeting APRIL and BAFF.
Cellular membrane-based vesicles displaying a reconstructed B cell maturation antigen for multiple myeloma therapy by dual targeting APRIL and BAFF.
复制标题
DOI：
10.1016/j.actbio.2022.02.028
复制
发表时间：
2022-02
影响因子：
9.7
通讯作者：
Chao He;Manqi Zhang;Lingling Liu;Yuhang Han;Zhanxue Xu;Yue Xiong;Fuxia Yan;Dandan Su;
中科院分区：
文献类型：
--
作者：
Chao He;Manqi Zhang;Lingling Liu;Yuhang Han;Zhanxue Xu;Yue Xiong;Fuxia Yan;Dandan Su;
骨髓微环境（BMM）中细胞因子（如APRIL和BAFF）的过度分泌在复发或难治性多发性骨髓瘤（MM）的形成中起重要作用。阻断过量细胞因子与其受体的结合正成为MM治疗的有希望的方法。在这里，我们提出了一种策略，工程细胞膜为基础的纳米囊泡（NV）重建B细胞成熟抗原（BCMA），APRIL和BAFF的受体，捕获过量的APRIL/BAFF BMM作为诱饵蛋白。我们的结果表明，在NVs膜上表达的重构BCMA（Re-BCMA-NVs）保留了与BMM中可溶性和表面结合的APRIL/BAFF结合的能力。因此，Re-BCMA-NV阻断NF-κB通路的活化，下调抗凋亡基因和细胞周期相关基因的表达，从而抑制MM细胞存活。重要的是，Re-BCMA-NV在体外和体内与硼替佐米（BTZ）一起给药时显示出协同抗MM作用。我们的靶向癌症微环境中多种细胞因子的NV为增强MM细胞对BTZ治疗的敏感性提供了解决方案。重要性声明据报道，过量的APRIL和BAFF可促进MM细胞的存活，并促进对硼替佐米治疗的耐药性形成。在这项研究中，我们生物工程细胞膜衍生的重构BCMA纳米囊泡（Re-BCMA-NVs）捕获可溶性和细胞表面的APRIL和BAFF。这些NV抑制NF-κB通路的活化，从而抑制MM细胞在2D、3D和皮下小鼠肿瘤模型中的存活。重要的是，Re-BCMA-NV在体外和体内与硼替佐米一起给药时显示出协同抗MM作用。总之，我们的靶向癌症微环境中多种细胞因子的NV提供了增强MM细胞对基于硼替佐米的疗法的敏感性的解决方案。
Excessive secretion of cytokines (such as APRIL and BAFF) in the bone marrow microenvironment (BMM) plays an essential role in the formation of relapsed or refractory multiple myeloma (MM). Blocking the binding of excessive cytokines to their receptors is becoming a promising approach for MM therapy. Here, we proposed a strategy of engineering cell membrane-based nanovesicles (NVs) to reconstruct B cell maturation antigen (BCMA), a receptor of APRIL and BAFF, to capture excess APRIL/BAFF in BMM as a bait protein. Our results showed that reconstructed BCMA expressed on the membrane of NVs (Re-BCMA-NVs) retained the ability of binding to soluble and surface-bound APRIL/BAFF in BMM. Consequently,Re-BCMA-NVs blocked the activation of the NF-κB pathway, downregulating the expression of anti-apoptosis genes and cell cycle-related genes, and hence inhibiting MM cell survival. Importantly,Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomib (BTZ)in vitroandin vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy.Statement of significanceExcessive APRIL and BAFF is reported to promote the survival of MM cell and facilitate the formation of resistance to bortezomib therapy. In this study, we bioengineered cell membrane derived reconstructed BCMA nanovesicles (Re-BCMA-NVs) to capture both soluble and cell-surface APRIL and BAFF. These NVs inhibited the activation of NF-κB pathway and thus inhibit the survival of MM cells in 2D, 3D and subcutaneous mouse tumor models. Importantly,Re-BCMA-NVs showed a synergistic anti-MM effect when administrated together with bortezomibin vitroandin vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.