Microenvironment-responsive hydrogels with drug-loaded microspheres for sustained dexamethasone acetate release and experimental autoimmune uveitis suppression

Experimental autoimmune uveitis (EAU) is a widely used model for non-infectious uveitis (NIU), a sight-threatening autoimmune ocular disease. Although glucocorticoids remain the first-line therapy, their short half-life and frequent administration increase the risk of systemic and ocular side effects. Here, we report the development of microenvironment-responsive hydrogels with drug-loaded microspheres for sustained dexamethasone acetate release: dexamethasone acetate-loaded microspheres (DAMS) and polyethylene glycol (PEG) hydrogel-encapsulated microspheres (DAMS@Gel). Poly(lactic-co-glycolic acid) (PLGA) microspheres were fabricated and subsequently embedded in pH-responsive and injectable hydrogels formed via Schiff base crosslinking. The materials were then thoroughly characterized. In vitro, both DAMS and DAMS@Gel exhibited excellent biocompatibility with retinal pigment epithelial (ARPE-19) cells, as confirmed by reactive oxygen species (ROS), apoptosis, cell cycle, and cytotoxicity assays. In vivo safety was verified through subconjunctival injection in rabbits. In the rat EAU model, intravitreal administration of DAMS and DAMS@Gel significantly alleviated ocular inflammation, as evidenced by ocular inflammatory symptom observations, fundus imaging, histopathological examination, and decreased glial activation. This study demonstrated that the DAMS and DAMS@Gel drug delivery systems were successfully established and exhibited sustained release properties and stable characteristics. In vitro and in vivo assays indicated that the biological materials had excellent biocompatibility. In addition, both DAMS and DAMS@Gel exerted therapeutic effects on the EAU model rats, and intraocular inflammation was reduced. This research provides a theoretical foundation for the treatment of uveitis with DAMS and DAMS@Gel.