Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting.
硼替佐米（BTZ）是多发性骨髓瘤（MM）的标准治疗药物；然而，其不良反应及耐药性的产生限制了其长期疗效。为提高靶向特异性、治疗效力并克服耐药性，我们设计了一种表面功能化BCMA抗体的纳米颗粒，用于封装BTZ（BCMA-BTZ-NPs）。我们证实，该纳米颗粒仅在表达BCMA的MM细胞中被高效内化，而在BCMA基因敲除（KO）细胞中则无此现象。此外，BCMA-BTZ-NPs对MM细胞系及患者来源的原代肿瘤细胞均表现出靶向特异性细胞毒性。该纳米颗粒通过受体介导的摄取进入细胞，从而规避了因P-糖蛋白上调引起的BTZ耐药机制。相比非靶向纳米颗粒或游离BTZ，BCMA-BTZ-NPs能更有效地诱导细胞死亡，引发强烈的线粒体去极化并随后启动细胞凋亡。在BTZ耐药细胞中，BCMA-BTZ-NPs对蛋白酶体活性的抑制效果优于游离BTZ或非靶向纳米颗粒。此外，与游离BTZ相比，BCMA-BTZ-NPs能增强免疫原性细胞死亡并更显著激活自噬通路。最终，在小鼠异种移植模型中，BCMA-BTZ-NPs选择性富集于肿瘤部位，增强肿瘤消退并延长宿主生存期。这些结果表明，BCMA-BTZ-NPs为提升BTZ疗效提供了具有前景的治疗策略，并为其临床评估建立了框架。
肿瘤(癌症)患者之家