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

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.