ROS-Triggered Disassembly of Nanoparticle-Networked Hydrogels Enables Dynamic Gating of Corneal Tight Junctions

Abstract

The blood-ocular barrier has always been a major challenge in the treatment of eye disease, such as fungal keratitis (FK). Herein, we report a reactive oxygen species (ROS)-triggered disassembly of nanoparticle-networked hydrogels enabling dynamic modulation of corneal tight junctions for enhanced drug bioavailability. The voriconazole (VCZ)-loaded fluorinated chitosan nanoparticles (FCS NPs) are incorporated as dynamic crosslinking nodes within a network formed by phenylboronic acid-modified alginate (SA-PBA) and poly vinyl alcohol (PVA), featuring a macroporous backbone interconnected by web-like nanofibrils. This hierarchical architecture functions as a protective, ROS-sacrificial matrix. In the oxidative microenvironment of FK, the hydrogel undergoes triggered disassembly via boronate ester oxidation, consuming ROS to ameliorate inflammation while liberating the FCS NPs. Once released, the exposed FCS acts as a permeation enhancer, temporarily opening tight junctions between corneal epithelial and endothelial cells via its interaction with cell membranes to facilitate deep stromal drug delivery. This process establishes a dynamic gating mechanism where barrier modulation is strictly confined to the infection site, maximizing therapeutic efficacy while ensuring biosafety. Animal experiments have shown that, compared with the clinically common 1% VCZ eye drops, RFV-Gel can achieve comparable or even superior antifungal effects at a lower drug concentration. This work establishes an effective cascade targeted paradigm for non-invasive ocular drug delivery.