The effectiveness of mucoadhesive drug delivery systems relies on the choice of the polymer, which typically adheres upon hydration. Selected polymers must maintain their adhesion to biological membranes and retain the drug for extended periods. Most hydrophilic polymers form weak non-covalent bonds, hindering the precise localization of dosage forms at target sites, resulting in suboptimal therapeutic outcomes. This limitation can be overcome by modifying natural polymers with thiol groups, known as thiomers. Thiomers offer enhanced stability across a wide pH range and prolonged residence at the intended targets.The primary objective of this study was to synthesize and characterize thiolated sodium alginate (TSA). Subsequently, etoricoxib-loaded microspheres were formulated using TSA, and the manufacturing process was optimized. The optimized formulation, denoted as MM-TSA, demonstrated complete and controlled drug release at the conclusion of dissolution testing. Cell viability assays confirmed the safety of both thiolated sodium alginate and the formulated microspheres. Furthermore, TSA exhibited significant mucoadhesive strength. These findings endorse S-protection as a promising strategy for enhancing the absorption of poorly water-soluble drugs like etoricoxib