A salivary amylase-responsive buccal tablet was developed to treat chemotherapy-induced refractory oral mucositis (OM). The tablet consists of porous manganese-substituted Prussian blue (PMPB) nanocubes (NCs), anti-inflammatory apremilast (Apr), and a starch controller. PMPB NCs, with a large surface area and multienzyme-mimicking activity, can scavenge reactive oxygen species (ROS) and deliver Apr, synergistically reducing inflammation. The starch controller responds to abundant salivary amylases (SAs) in the oral cavity, enabling cascade, continuous, and complete drug release. This design enhances tissue affinity, prolongs resistance time, and improves patient comfort. Preclinical studies show that the tablet mitigates inflammation, promotes endothelial proliferation and migration, and accelerates wound healing, effectively treating OM with a positive oral microenvironment and shorter recovery time. The tablet is biosafe, FDA-approved, and offers a promising clinical translation. The study highlights the importance of enzyme-responsive drug delivery systems in improving therapeutic outcomes for OM, which is a common and severe complication of cancer chemotherapy and radiotherapy. The developed buccal tablet demonstrates high efficacy in reducing inflammation and promoting wound healing, with excellent mechanical properties and biosafety. The results suggest that the SAs-responsive buccal tablet is a promising candidate for clinical application in treating OM.A salivary amylase-responsive buccal tablet was developed to treat chemotherapy-induced refractory oral mucositis (OM). The tablet consists of porous manganese-substituted Prussian blue (PMPB) nanocubes (NCs), anti-inflammatory apremilast (Apr), and a starch controller. PMPB NCs, with a large surface area and multienzyme-mimicking activity, can scavenge reactive oxygen species (ROS) and deliver Apr, synergistically reducing inflammation. The starch controller responds to abundant salivary amylases (SAs) in the oral cavity, enabling cascade, continuous, and complete drug release. This design enhances tissue affinity, prolongs resistance time, and improves patient comfort. Preclinical studies show that the tablet mitigates inflammation, promotes endothelial proliferation and migration, and accelerates wound healing, effectively treating OM with a positive oral microenvironment and shorter recovery time. The tablet is biosafe, FDA-approved, and offers a promising clinical translation. The study highlights the importance of enzyme-responsive drug delivery systems in improving therapeutic outcomes for OM, which is a common and severe complication of cancer chemotherapy and radiotherapy. The developed buccal tablet demonstrates high efficacy in reducing inflammation and promoting wound healing, with excellent mechanical properties and biosafety. The results suggest that the SAs-responsive buccal tablet is a promising candidate for clinical application in treating OM.