Hyaluronic acid-functionalized PLGA nanoparticles loaded with circSNX6 siRNA overcome sunitinib resistance in renal cell carcinoma

Abstract

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.