Small interfering RNA (siRNA) exhibits great potential as a novel therapeutic option due to its highly sequence-specific ability to silence genes. However, efficient and safe delivery carriers are required for developing novel therapeutic paradigms. Thus, the successful development of efficient delivery platforms for siRNA is a crucial issue for the development of siRNA-based drugs in cancer treatments. In this study, biocompatible selenium nanoparticles (SeNPs) were loaded with RGDfC peptide to fabricate tumor-targeting gene delivery vehicle RGDfC-SeNPs. Subsequently, RGDfC-SeNPs were loaded with Derlin1-siRNA to fabricate RGDfC-Se@siRNA, which are functionalized selenium nanoparticles. RGDfC-Se@siRNA showed greater uptake in HeLa cervical cancer cells in comparison with that in human umbilical vein endothelial cells (HUVECs), verifying the RGDfC-mediated specific uptake of RGDfC-Se@siRNA. RGDfC-Se@siRNA was capable of entering HeLa cells via clathrin-associated endocytosis, and showed faster siRNA release in a cancer cell microenvironment in comparison with a normal physiological environment. qPCR and western blotting assays both indicated that RGDfC-Se@siRNA exhibited an obvious gene silencing efficacy in HeLa cells. RGDfC-Se@siRNA suppressed the invasion, migration and the proliferation of HeLa cells, and triggered HeLa cell apoptosis. Moreover, RGDfC-Se@siRNA induced the disruption of mitochondrial membrane potentials. Meanwhile, RGDfC-Se@siRNA enhanced the generation of reactive oxygen species (ROS) in HeLa cell, suggesting that mitochondrial dysfunction mediated by ROS might play a significant role in RGDfC-Se@siRNA-induced apoptosis. Interestingly, RGDfC-SeNPs@siRNA exhibited significant antitumor activity in a HeLa tumor-bearing mouse model. Additionally, RGDfC-SeNPs@siRNA is nontoxic to main organ of mouse. The above results indicate that RGDfC-Se@siRNA provides a promising potential for cervical cancer therapy.

中文翻译：

---

靶向siRNA的功能化硒纳米粒子可沉默Derlin1并提高抗宫颈癌的抗肿瘤功效。

小干扰RNA（siRNA）由于具有高度序列特异性的沉默基因能力，因此具有作为新型治疗选择的巨大潜力。然而，开发新型治疗范例需要有效和安全的递送载体。因此，成功开发有效的siRNA递送平台是在癌症治疗中开发基于siRNA的药物的关键问题。在这项研究中，将生物相容性硒纳米颗粒（SeNPs）装入RGDfC肽，以制备靶向肿瘤的基因递送载体RGDfC-SeNPs。随后，RGDfC-SeNPs上装有Derlin1-siRNA，以制造RGDfC-Se @ siRNA，这是功能化的硒纳米颗粒。与人脐静脉内皮细胞（HUVEC）相比，RGDfC-Se @ siRNA在HeLa宫颈癌细胞中的摄取更大，验证RGDfC介导的RGDfC-Se @ siRNA的特异性摄取。RGDfC-Se @ siRNA能够通过网格蛋白相关的内吞作用进入HeLa细胞，与正常的生理环境相比，在癌细胞微环境中显示出更快的siRNA释放。qPCR和Western blotting分析均表明RGDfC-Se @ siRNA在HeLa细胞中表现出明显的基因沉默功效。RGDfC-Se @ siRNA抑制HeLa细胞的侵袭，迁移和增殖，并触发HeLa细胞凋亡。此外，RGDfC-Se @ siRNA诱导线粒体膜电位的破坏。同时，RGDfC-Se @ siRNA增强了HeLa细胞中活性氧（ROS）的生成，提示ROS介导的线粒体功能障碍可能在RGDfC-Se @ siRNA诱导的细胞凋亡中起重要作用。有趣的是 RGDfC-SeNPs @ siRNA在带有HeLa肿瘤的小鼠模型中显示出显着的抗肿瘤活性。另外，RGDfC-SeNPs @ siRNA对小鼠的主要器官无毒。以上结果表明RGDfC-Se @ siRNA为宫颈癌治疗提供了有希望的潜力。