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-<i>co</i>-glycolic acid) (PLGA) microspheres were fabricated and subsequently embedded in pH-responsive and injectable hydrogels formed <i>via</i> Schiff base crosslinking. The materials were then thoroughly characterized. <i>In vitro</i>, 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. <i>In vivo</i> 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. <i>In vitro</i> and <i>in vivo</i> 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.