Dual Ferroptosis-Inhibitory and Antifungal Therapy for Fungal Keratitis Using a Defect-Adhesive Thermoresponsive...

Area of Science:

• Ophthalmology
• Biomaterials Science
• Pharmacology

Background:

• Fungal keratitis causes corneal blindness and is challenging to treat due to poor drug retention and limited therapeutic mechanisms.
• Current treatments primarily target fungal infections, often overlooking critical pathways like inflammation, fibrosis, and cell death.

Purpose of the Study:

• To develop a synergistic therapeutic strategy for fungal keratitis by targeting ferroptosis, a key pathogenic mechanism.
• To create a novel thermosensitive hydrogel for sustained co-delivery of an antifungal agent and a ferroptosis inhibitor.

Main Methods:

• A thermosensitive in situ-forming hydrogel (PX/HA/Fer-1/VOR) was formulated using poloxamer and hyaluronic acid.
• The hydrogel co-delivered ferrostatin-1 (Fer-1, ferroptosis inhibitor) and voriconazole (VOR, antifungal agent).
• In vitro and in vivo models of fungal keratitis were used to evaluate therapeutic efficacy, corneal retention, and mechanism of action.

Main Results:

• The PX/HA/Fer-1/VOR hydrogel demonstrated lens-like adhesion, enhancing corneal retention for over 90 minutes.
• In vivo studies showed superior efficacy compared to conventional voriconazole eye drops, with a single daily application suppressing inflammation, reducing fibrosis, and promoting visual recovery.
• The hydrogel achieved synergistic effects via zinc ion chelation, ferroptosis inhibition, and fibrosis attenuation.

Conclusions:

• This multifunctional hydrogel platform offers a promising, sustained-release therapeutic strategy for fungal keratitis.
• The approach effectively targets multiple pathogenic pathways, including fungal growth, ferroptosis, inflammation, and fibrosis.
• The study highlights the potential of advanced hydrogel systems in managing complex ocular infections and improving patient outcomes.