Gao Yue, Li Zhen, Wang Xuelian, Chen Simeng, Li Pengcheng, Tie Xiaowei, Zhang Lu, Zhang Hongjiang, Wang Jin, Wang Yong
Department of Oncology, The First Hospital of Anhui University of Science and Technology, Huainan, 232002, China.
Department of Urology, Beijing Chaoyang Hospital Affiliated Capital Medical University, 8 Gong Ti Nan Road, Chaoyang District, Beijing, 100020, China.
Biochem Biophys Res Commun. 2025 Aug 30;776:152226. doi: 10.1016/j.bbrc.2025.152226. Epub 2025 Jun 17.
Addressing the challenge of sunitinib resistance in renal cell carcinoma (RCC), while multiple molecular targets have been identified to enhance RCC's response to sunitinib, effective therapeutic strategies remain largely unidentified. Previous studies have highlighted those elevated levels of circular RNA circSNX6, a key regulator of circSNX6/miR-1184/GPCPD1 axis had a critical role in regulation of intracellular lysophosphatidic acid (LPA) levels and sunitinib resistance in RCC. Therefore, there is an urgent need for innovative treatment strategies to combat sunitinib resistance. In this study, we developed hyaluronic acid-modified poly (lactic-co-glycolic acid) nanoparticles (HA-PLGA-NPs) loaded with circSNX6 small interfering RNA (siRNA), designed as a targeted delivery system to overcome drug resistance in RCC. Compared to CD44-negative cells, HA-PLGA-NPs demonstrated markedly improved binding affinity to CD44-positive RCC cells, thereby enhancing their sensitivity to sunitinib. RNA sequencing (RNA-seq) data revealed that circSNX6 knockdown promoted apoptosis, induced mitochondrial changes, and negatively regulated the organization of mitochondrion. In an RCC xenograft model with established sunitinib resistance, the injection of HA-PLGA-NPs carrying circSNX6 siRNA effectively reversed this resistance. These results reveal a novel molecular mechanism through which circSNX6 mediates sunitinib resistance in RCC, and suggest that HA-PLGA-NPs could represent a promising and selective approach for overcoming this resistance.
为应对肾细胞癌（RCC）中舒尼替尼耐药的挑战，虽然已确定多个分子靶点以增强RCC对舒尼替尼的反应，但有效的治疗策略在很大程度上仍未明确。先前的研究强调，环状RNA circSNX6水平升高，circSNX6/miR-1184/GPCPD1轴的关键调节因子在调节RCC细胞内溶血磷脂酸（LPA）水平和舒尼替尼耐药中起关键作用。因此，迫切需要创新的治疗策略来对抗舒尼替尼耐药。在本研究中，我们开发了负载circSNX6小干扰RNA（siRNA）的透明质酸修饰聚（乳酸-乙醇酸）纳米颗粒（HA-PLGA-NPs），设计为一种靶向递送系统以克服RCC中的耐药性。与CD44阴性细胞相比，HA-PLGA-NPs对CD44阳性RCC细胞表现出明显改善的结合亲和力，从而增强它们对舒尼替尼的敏感性。RNA测序（RNA-seq）数据显示，circSNX6敲低促进细胞凋亡，诱导线粒体变化，并对线粒体的组织起负调节作用。在已建立舒尼替尼耐药的RCC异种移植模型中，注射携带circSNX6 siRNA的HA-PLGA-NPs有效逆转了这种耐药性。这些结果揭示了circSNX6介导RCC中舒尼替尼耐药的一种新分子机制，并表明HA-PLGA-NPs可能是克服这种耐药性的一种有前景的选择性方法。
