Disulfide-Appended siRNA Nanoeyedrops: Noninvasive Gene Therapy for Targeting Retinal Angiogenesis.

Abstract

Given the significant advantages the eye presents as a target organ for gene therapy, it has remained at the forefront of translational research in this field. However, gene delivery to the desired tissue, particularly the retina, via a noninvasive route of administration poses a substantial physical challenge due to the presence of multiple ocular barriers. Here, we develop disulfide-appended small interfering RNA (DS-siRNA) Nanoeyedrops that target pathological retinal angiogenesis. These Nanoeyedrops enable noninvasive and effective gene delivery into the retina through the thiol-mediated uptake route. We have demonstrated that the thiol-mediated uptake route represents a powerful approach capable of overcoming ocular barriers. Ultimately, we have applied these Nanoeyedrops to deliver VEGF siRNA, which has exhibited substantial effects in both choroidal neovascularization and retinoblastoma mouse models. It serves as a highly efficient delivery system that enables noninvasive ocular gene delivery with high bioavailability, thereby offering a promising strategy for treating retinal diseases.