Oral mucositis (OM) is a common and refractory complication of cancer chemotherapy and radiotherapy, significantly impacting patients' quality of life and treatment tolerance. Current OM delivery systems often suffer from poor patient compliance and unsatisfactory outcomes. This study introduces salivary amylases (SAs)-responsive buccal tablets containing porous manganese-substituted Prussian blue (PMPB) nanocubes, anti-inflammatory apremilast (Apr), and starch. PMPB nanocubes, with their large surface area and multienzyme activity, scavenge reactive oxygen species (ROS) and synergize with Apr to mitigate inflammation. The starch controller responds to SAs in the oral cavity, enabling a continuous and complete drug release, enhancing tissue affinity and comfort. Preclinical studies show that these buccal tablets effectively reduce inflammation, promote endothelial cell proliferation and migration, and accelerate wound healing, demonstrating potential for clinical translation in treating chemotherapy-induced OM.Oral mucositis (OM) is a common and refractory complication of cancer chemotherapy and radiotherapy, significantly impacting patients' quality of life and treatment tolerance. Current OM delivery systems often suffer from poor patient compliance and unsatisfactory outcomes. This study introduces salivary amylases (SAs)-responsive buccal tablets containing porous manganese-substituted Prussian blue (PMPB) nanocubes, anti-inflammatory apremilast (Apr), and starch. PMPB nanocubes, with their large surface area and multienzyme activity, scavenge reactive oxygen species (ROS) and synergize with Apr to mitigate inflammation. The starch controller responds to SAs in the oral cavity, enabling a continuous and complete drug release, enhancing tissue affinity and comfort. Preclinical studies show that these buccal tablets effectively reduce inflammation, promote endothelial cell proliferation and migration, and accelerate wound healing, demonstrating potential for clinical translation in treating chemotherapy-induced OM.