The antioxidant effect of tetrahedral framework nucleic acid‐based delivery of small activating RNA targeting DJ‐1 on retinal oxidative stress injury

Age‐related macular degeneration (AMD) and diabetic retinopathy (DR) are the world's leading causes of blindness. The retinal pigment epithelium (RPE) and vascular endothelial cell exposed to oxidative stress is the major cause of AMD and DR. DJ‐1, an important endogenous antioxidant, its overexpression is considered as a promising antioxidant treatment for AMD and DR. Here, we modified the tetrahedral frame nucleic acids (tFNAs) with DJ‐1 saRNAs as a delivery system, and synthesized a novel nanocomplex (tFNAs‐DJ‐1 saRNAs). In vitro studies show that tFNAs‐DJ‐1 saRNAs can efficiently transfer DJ‐1 saRNAs to human umbilical vein endothelial cells (HUVECs) and ARPE‐19s, and significantly increased their cellular DJ‐1 level. Reactive oxygen species expression in H2O2‐treated HUVECs and ARPE‐19s were decreased, cell viability was enhanced and cell apoptosis were inhibited when tFNAs‐DJ‐1 saRNAs were delivered. Moreover, tFNAs‐DJ‐1 saRNAs preserved mitochondrial structure and function under oxidative stress conditions. In the aspect of molecular mechanism, tFNAs‐DJ‐1 saRNAs activated Erk and Nrf2 pathway, which might contribute to its protective effects against oxidative stress damage. To conclude, this study shows the successfully establishment of a simple but effective delivery system of DJ‐1 saRNAs associated with antioxidant effects in AMD and DR, which may be a promising agent for future treatment in oxidative stress‐related retinal disorders. Illustration of the preparation of tFNAs‐DJ‐1 saRNAs complex and its anti‐oxidative effects on human umbilical vein endothelial cells (HUVECs) and ARPE‐19.