Endothelia-targeting eye drops deliver a STING inhibitor to effectively reduce retinal neovascularization in ischemic retinopathy

Retinal neovascularization is the main pathologic feature of ischemic retinopathy, which eventually leads to vision loss and even blindness. Current treatments like laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor A (VEGFA) drugs are invasive, expensive, and incompetent. Therefore, it is urgent to explore optimized therapies, particularly eye drops, to improve treatment effects. Our recent study reported that abnormal activation of the stimulator of interferon genes (STING) is closely associated with retinal vascular diseases, and it is highly enriched in retinal endothelial cells (ECs) with retinopathy. Thus, we evaluated whether endothelial STING affects retinal neovascularization. In addition, we constructed iRGD- and TAT-decorated nanoparticles (NPs) loaded with C-176 (I/T-C-NP), capable of penetrating the cornea and targeting retinal ECs. The I/T-C-NP eye drops were applied to the eyes of oxygen-induced retinopathy (OIR) mice, resulting in attenuated activation of the STING pathway. Consequently, retinal neovascularization and vascular tortuosity were effectively reduced, astrocyte activation was prohibited, and pericyte coverage was improved. These observations suggest that I/T-C-NP eye drops can be a potential solution for the treatment of retinal neovascularization.