Department of Laboratory Medicine, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Blood Transfusion, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
J Nanobiotechnology. 2023 Mar 14;21(1):89. doi: 10.1186/s12951-023-01840-3.
Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal-organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC.
需要寻找策略来克服针对肝细胞癌 (HCC) 的靶向治疗中化疗药物引起的毒性和耐药性。先前的研究表明，HCC 中高氧化还原硝基结构域包含蛋白 1（NOR1）的表达与顺铂（DDP）耐药有关。在此，为治疗 HCC 的 DDP 耐药性，生成了一种新型的双重靶向纳米载体系统 AR-NADR。纳米载体系统的核心是经过核定位序列（NLS）修饰的金属有机骨架（MOF），其负载 DDP 和 NOR1 shRNA（R）。外壳是插入红细胞膜（AR）的 A54 肽。我们的结果表明，由于其与 HCC 细胞表面大量表达的 A54 受体的特异性结合以及 NLS 肽介导的核内进入，AR-NADR 可有效地被肿瘤细胞内化。此外，由于酸性肿瘤微环境中 Ag-MOF 的降解，DDP 更有可能被释放。此外，通过充当基因传递载体，AR-NADR 通过抑制 NOR1 的表达有效抑制肿瘤耐药性，从而诱导细胞内 DDP 积累并使细胞对 DDP 敏感。最后，通过 HepG2/DDP 细胞模型和肿瘤模型系统地阐明了 AR-NADR 的抗 HCC 功效和机制。因此，AR-NADR 构成了实现优异基因沉默和抗肿瘤功效的关键策略，为 HCC 的顺铂耐药性提供了有效的基因治疗和精确的治疗策略。
