He Chao, Zhang Manqi, Liu Lingling, Han Yuhang, Xu Zhanxue, Xiong Yue, Yan Fuxia, Su Dandan, Chen Hongbo, Zheng Yongjiang, Cheng Fang
School of pharmaceutical sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.
Department of Hematology, Institute of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, Guangdong, China.
Acta Biomater. 2022 Apr 15;143:406-417. doi: 10.1016/j.actbio.2022.02.028. Epub 2022 Feb 24.
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 vitro and in vivo. Our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to BTZ-based therapy. STATEMENT OF SIGNIFICANCE: Excessive 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 bortezomib in vitro and in vivo. Taken together, our NVs targeting multiple cytokines in cancer microenvironment provides a solution to enhance sensitivity of MM cells to bortezomib-based therapy.
骨髓微环境（BMM）中细胞因子（如增殖诱导配体（APRIL）和B细胞活化因子（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治疗的一种有前景的方法。在此，我们提出了一种基于细胞膜的纳米囊泡（NVs）工程策略，以重建APRIL和BAFF的受体——B细胞成熟抗原（BCMA），作为诱饵蛋白捕获BMM中过量的APRIL/BAFF。我们的结果表明，在NVs膜上表达的重组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-NVs阻断了核因子κB（NF-κB）途径的激活，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-NVs在体外和体内与硼替佐米（BTZ）联合给药时显示出协同抗MM作用。我们针对癌症微环境中多种细胞因子的NVs为提高MM细胞对基于BTZ治疗的敏感性提供了一种解决方案。意义声明：据报道，过量的APRIL和BAFF可促进MM细胞存活并促进对硼替佐米治疗的耐药性形成。在本研究中，我们通过生物工程改造细胞膜来源的重组BCMA纳米囊泡（Re-BCMA-NVs）来捕获可溶性和细胞表面的APRIL和BAFF。这些NVs在二维、三维和皮下小鼠肿瘤模型中抑制了NF-κB途径的激活，从而抑制了MM细胞的存活。重要的是，Re-BCMA-NVs在体外和体内与硼替佐米联合给药时显示出协同抗MM作用。综上所述，我们针对癌症微环境中多种细胞因子的NVs为提高MM细胞对基于硼替佐米治疗的敏感性提供了一种解决方案。
