Unveiling the Power of Gabapentin-Loaded Nanoceria with Multiple Therapeutic Capabilities for the Treatment of Dry Eye Disease

Dry eye (DE) disease, which is primarily linked to aqueous deficiency, is an escalating health issue worldwide, mainly due to the widespread use of electronic devices. The major obstacles in DE pharmacotherapy include insufficient therapeutic efficacy and low ocular bioavailability. This study presents the development of a ceria-based nanosystem to carry gabapentin (GBT), aiming to offer comprehensive relief from DE symptoms. We prepared multifunctional nanoceria capped with thiolated gelatin followed by cross-linking with glutaraldehyde, yielding a nanocarrier with desirable biocompatibility and antioxidant, anti-inflammatory, antiangiogenic, antiapoptotic, and neuronal protective activities. Specifically, the highly abundant thiol groups on gelatin increased the cellular uptake of the nanocarrier by 2.3-fold and its mucin-binding efficiency by 10-fold, thereby extending ocular retention and amplifying therapeutic activity. Moderate cross-linking of the thiolated gelatin not only enhanced the ocular bioavailability of the nanoceria but also provided slow, degradation-controlled release of GBT to promote the lacrimal stimulation to restore the tear film. In a rabbit model of DE, topical administration of our GBT/nanoceria nanoformulation resulted in comprehensive alleviation of symptoms, including repairing corneal epithelial damage, preserving corneal nerve density, and stimulating tear secretion, demonstrating superior performance in comparison to the free drug. These results underscore the safety and potential of this innovative nanoformulation for DE pharmacotherapy.