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

Area of Science:

• Biomaterials Science
• Ophthalmology
• Drug Delivery

Background:

• The blood-ocular barrier presents a significant challenge for treating eye diseases like fungal keratitis (FK).
• Effective drug delivery to the cornea is crucial for managing ocular infections.
• Existing treatments often struggle with bioavailability and targeted delivery.

Purpose of the Study:

• To develop a novel nanoparticle-networked hydrogel system for triggered drug release and enhanced corneal drug penetration.
• To investigate the potential of ROS-triggered hydrogel disassembly for modulating corneal tight junctions.
• To evaluate the efficacy of the developed system for treating fungal keratitis in preclinical models.

Main Methods:

• Fabrication of a hierarchical hydrogel incorporating voriconazole-loaded fluorinated chitosan nanoparticles (FCS NPs) within an alginate-phenylboronic acid and polyvinyl alcohol network.
• Utilizing the oxidative microenvironment of FK to trigger hydrogel disassembly via boronate ester oxidation, consuming ROS.
• Assessing the release of FCS NPs and their role as permeation enhancers to open corneal tight junctions for deep stromal drug delivery.
• Evaluating the antifungal efficacy and biosafety of the RFV-Gel system in animal models compared to conventional eye drops.

Main Results:

• The nanoparticle-networked hydrogel demonstrated ROS-triggered disassembly, ameliorating inflammation and releasing FCS NPs.
• Released FCS NPs acted as permeation enhancers, temporarily opening corneal tight junctions for improved drug delivery.
• RFV-Gel achieved comparable or superior antifungal effects to 1% voriconazole eye drops at lower concentrations in animal studies.
• The system established a dynamic gating mechanism for targeted drug delivery, confined to the infection site.

Conclusions:

• The developed ROS-triggered hydrogel system offers a promising strategy for overcoming the blood-ocular barrier in fungal keratitis treatment.
• This approach enhances drug bioavailability and therapeutic efficacy through dynamic modulation of corneal permeability.
• The study presents an effective cascade-targeted paradigm for non-invasive ocular drug delivery, improving treatment outcomes for fungal eye infections.