Tetrahedral Framework Nucleic Acid‐Based Delivery of DJ‐1‐saRNA Prevent Retinal Ischaemia–Reperfusion Injury via Inhibiting Ferroptosis

ABSTRACT Retinal ischaemia/reperfusion injury (RI/RI) is the primary pathophysiological mechanism underlying retinal ischaemic diseases, potentially resulting in significant and irreversible visual impairment. Currently, there are no effective treatments available for RI/RI, and oxidative stress is a critical factor that contributes to the associated damage. DJ‐1, an important endogenous antioxidant, has been proposed as a promising therapeutic agent for RI/RI owing to its potential for overexpression. In this study, tetrahedral frame nucleic acids (tFNAs) were utilised as an effective delivery vehicle for DJ‐1 small activating RNA (saRNA), resulting in the synthesis of a novel nanocomposite (tFNAs‐DJ‐1‐saRNA). In vitro experiments demonstrated that tFNAs effectively delivered DJ‐1‐saRNA to R28 cells, thus exerting a repair effect on oxidative stress injury. In vivo investigations revealed that the intravitreal injection of tFNAs‐DJ‐1‐saRNA facilitated retinal DJ‐1 gene expression and mitigated retinal atrophy induced by RI/RI. Mechanistically, tFNAs‐DJ‐1‐saRNA activated the xCT/GPX4 pathway, thereby inhibiting ferroptosis, reducing ganglion cell damage and protecting the retinal tissue. In conclusion, this study demonstrated that the tFNAs‐DJ‐1‐saRNA complex can ameliorate RI/RI by inhibiting ferroptosis, suggesting its potential as a novel agent for the treatment of retinal ischaemic diseases.