Objective To develop a lycium barbarum glycopeptide(LbGP) spray based on oxidized sodium alginate(OSA) and gelatin microspheres to alleviate tobacco combustion product-induced oral mucositis. Methods ①Cigarette smoke extract(CSE) was prepared and screened for the optimal intervention concentration through CCK-8 assay. ②LbGP-loaded gelatin microspheres and OSA matrix were fabricated, characterizing morphology, oxidation degree, and physicochemical properties. ③pH, sustained-release capability, stability, and adhesion of LbGP-OSA spray were evaluated. ④The protective and antioxidant effects of the spray on tobacco-damaged human gingival fibroblasts(HGFs)were assessed by CCK-8 assay, live/dead staining, scratch assay, ROS, and GSH detection. ⑤A smoking rat oral mucositis model was established to analyze the healing efficacy through ulcer recovery, HE/Masson staining, and immunohistochemistry. Results ①LbGP-OSA spray exhibited an oxidation degree of 29.17%±2.46%, with microsphere size (13.3±2.3)μm, pH=6.8, and favorable sustained-release/adhesion properties. ②The spray significantly improved HGFs viability and migration, reduced ROS levels, and elevated GSH content. ③In rats, the spray accelerated mucositis healing(epithelial integrity restored at day 9), down-regulated TNF-α and IL-6(P<0.05), up-regulated IL-10(P<0.05), and showed no toxicity. Conclusion The LbGP-OSA spray demonstrates sustained-release capability, adhesion, and biocompatibility, mitigates oxidative damage, modulates inflammatory cytokines, promotes mucosal healing, and holds clinical potential for tobacco-related oral injuries.