Ocular topical aesculetin delivery via VA64/TPGS co-assembled micelles for redox-inflammatory modulation in...

Cataract progression is closely associated with oxidative stress and inflammatory activation, while effective non-surgical interventions remain limited. Aesculetin (AES) possesses antioxidant and anti-inflammatory activities, but its topical ophthalmic application is restricted by poor aqueous solubility, insufficient dispersion stability, and limited local availability. Here, AES-loaded VA64/TPGS co-assembled micelles (AES@V-T) were developed as a topical ophthalmic delivery system. The optimized AES@V-T showed a mean particle size of 13.10 ± 0.16 nm, a narrow polydispersity index of 0.094 ± 0.020, and an encapsulation efficiency above 99%, indicating the formation of a uniform nanoscale colloidal system with efficient drug incorporation. Compared with free AES, AES@V-T increased the apparent solubility of AES in artificial tears by 501-fold and enhanced its 12 h cumulative release from 9.32% to 59.84%. Cou-6 incorporated into the AES@V-T formulation produced stronger corneal-associated fluorescence than the free probe, providing qualitative evidence of improved corneal presentation of a model hydrophobic payload. In an ex vivo post-exposure lens injury model, AES@V-T preserved lens transparency and attenuated abnormal swelling. Topical administration of AES@V-T also markedly attenuated cataract development in sodium selenite-treated rat pups. Biochemical analyses showed that AES@V-T reduced lipid peroxidation and oxidative DNA damage, improved endogenous antioxidant defenses, and decreased the lens levels of HMGB1, total NF-κB p65, and pro-inflammatory cytokines, consistent with attenuation of the inflammatory-marker profile associated with sodium selenite-induced injury. These findings indicate that VA64/TPGS co-assembly improved the aqueous formulation state and topical ocular performance of AES, supporting its enhanced protection against sodium selenite-induced lens injury.