靶向耐药化疗的影响因素是增强化学治疗药物有效性的一种途径。在慢性淋巴细胞白血病（CLL）细胞中，核因子红细胞2相关因子2（Nrf2）途径过度表达，并且似乎在细胞的生存和化疗耐药中起到重要作用。本研究针对CD20表达的CLL细胞产生了新的特异性纳米颗粒（NPs），同时具有抗-Nrf2和细胞毒作用。使用乳酸凝霉素（CL）制备了原始纳米颗粒，然后分别装载了利妥昔单抗（RTX）、抗-Nrf2的小干扰RNA（siRNA）和环磷酰胺（CP）来制备最终版本的纳米颗粒（NP-Nrf2_siRNA-CP）。所有干预措施都在外周血单个核细胞（PBMCs）和骨髓单个核细胞（BMNCs）上进行。NP-Nrf2_siRNA-CP具有令人满意的物理化学特性，显示了可控的抗-Nrf2 siRNA/CP释放，并且能够高效转染CLL原代细胞（包括PBMCs和BMNCs）。NP-Nrf2_siRNA-CP能够显著诱导细胞凋亡和抑制增殖，表现为分别降低抗凋亡因子和增加促凋亡因子。此外，使用抗-Nrf2 siRNA与CP相结合，使CLL细胞对CP的敏感性增加。我们的研究结果表明，RTX、CP和抗-Nrf2 siRNA的联合治疗是一种新颖而高效的治疗策略，能够破坏恶性CLL细胞。此外，纳米颗粒作为多重药物输送方法表现出了令人满意的特性，但需要进一步的研究。视频摘要。© 2023.作者。

Targeting influential factors in resistance to chemotherapy is one way to increase the effectiveness of chemotherapeutics. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway overexpresses in chronic lymphocytic leukemia (CLL) cells and appears to have a significant part in their survival and chemotherapy resistance. Here we produced novel nanoparticles (NPs) specific for CD20-expressing CLL cells with simultaneous anti-Nrf2 and cytotoxic properties.Chitosan lactate (CL) was used to produce the primary NPs which were then respectively loaded with rituximab (RTX), anti-Nrf2 Small interfering RNA (siRNAs) and Cyclophosphamide (CP) to prepare the final version of the NPs (NP-Nrf2_siRNA-CP). All interventions were done on both peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BMNCs).NP-Nrf2_siRNA-CP had satisfying physicochemical properties, showed controlled anti-Nrf2 siRNA/CP release, and were efficiently transfected into CLL primary cells (both PBMCs and BMNCs). NP-Nrf2_siRNA-CP were significantly capable of cell apoptosis induction and proliferation prevention marked by respectively decreased and increased anti-apoptotic and pro-apoptotic factors. Furthermore, use of anti-Nrf2 siRNA was corresponding to elevated sensitivity of CLL cells to CP.Our findings imply that the combination therapy of malignant CLL cells with RTX, CP and anti-Nrf2 siRNA is a novel and efficient therapeutic strategy that was capable of destroying malignant cells. Furthermore, the use of NPs as a multiple drug delivery method showed fulfilling properties; however, the need for further future studies is undeniable. Video Abstract.© 2023. The Author(s).