Fluorinated ROS-responsive polycation enables noninvasive siRNA Delivery for the treatment of corneal neovascularization.

Abstract

Corneal neovascularization (CNV) is a vision-threatening condition characterized by abnormal blood vessel growth into the avascular cornea, impairing its transparency and visual function. CNV is driven by an imbalance between pro- and anti-angiogenic factors, notably the overexpression of vascular endothelial growth factor (VEGF), exacerbated by inflammation and oxidative stress. Current treatments, including anti-VEGF and anti-inflammatory agents, are limited by poor bioavailability and invasive administration. In this study, we developed a fluorinated polycation for non-invasive delivery of siVEGFA along with ROS scavenging functionality to combat CNV. This multifunctional polymer exhibits enhanced ocular surface penetration via fluorination effect, efficient siRNA binding and delivery, and ROS-scavenging capacity. It demonstrated high biocompatibility, suppressed VEGFA expression, and significantly inhibited CNV progression in a mouse alkali burn model. These results highlight the promise of fluorinated, stimuli-responsive polymers as a dual-functional platform for safe, effective, and non-invasive treatment of ocular neovascular disorders. STATEMENT OF SIGNIFICANCE: CNV is a major cause of vision loss, yet current treatments rely on invasive injections or anti-inflammatory drugs, which can hinder corneal healing and reduce patient compliance. This study presents a fluorinated, ROS-responsive polycation that enables non-invasive, topical siRNA delivery while simultaneously combatting oxidative stress. Unlike conventional carriers, fluorination improves ocular penetration and intracellular delivery. By combining VEGFA knockdown with intrinsic antioxidant activity, this platform effectively suppresses neovascularization without delaying epithelial repair. This study advances the field of ocular gene therapy by offering a safer, injection-free alternative. It also highlights the potential of multifunctional polymer systems for treating chronic ocular vascular diseases.