Zn2+-Cross-Linked Polyelectrolyte Complexes Based on Diethylaminoethyl Chitosan and Dextran Sulfate for Sustained Delivery of Dexamethasone Phosphate

Dexamethasone phosphate (DexP) is a potent glucocorticoid limited by rapid clearance and a short half-life. To enable sustained DexP delivery, we developed polyelectrolyte complexes based on chitosan (CS) or diethylaminoethyl chitosan (DeaeCS) cross-linked with dextran sulfate (DS) via Zn2+ ions, which are proposed to form coordination bonds with sulfate, phosphate, and amino groups, creating a denser hybrid matrix. The resulting spherical particles (132–180 nm) exhibited tunable surface charge (−23.0 to +28.3 mV) and high encapsulation efficiency (up to 100%). XRD indicated amorphization of DexP within the matrix. In vitro release in simulated tear fluid showed that both Zn2+ cross-linking and DeaeCS significantly prolonged release. The optimized DexP-DS-DeaeCS-Zn-10 formulation achieved 1.5-fold higher corneal permeability (Papp = 14.28 × 10−6 cm/s) compared to free DexP while maintaining low cytotoxicity in SIRC and THP-1 cells. Encapsulated DexP effectively suppressed TNF-α-induced CD54 expression in macrophages, confirming preserved anti-inflammatory activity. These hybrid particles combine sustained release, enhanced corneal penetration, and Zn2+-mediated anti-inflammatory effects, representing a promising platform for improved DexP delivery.