| Summary: | Abstract Oral mucositis (OM) is the most common and refractory complication of cancer chemotherapy and radiotherapy, severely affecting patients’ life quality, lowering treatment tolerance, and discouraging patient compliance. Current OM delivery systems mostly affect the comfort of patient use and lead to poor compliance and unsatisfactory effects. Herein, salivary amylases (SAs)‐responsive buccal tablets consisting of porous manganese‐substituted Prussian blue (PMPB) nanocubes (NCs), anti‐inflammatory apremilast (Apr) and starch controller have been engineered. PMPB NCs with large surface area can serve as carriers to load Apr, and their multienzyme‐mimicking activity enables them to scavenge reactive oxygen species (ROS), which thus synergize with Apr to mitigate inflammation. More significantly, the starch controller can respond to abundant SAs in the oral cavity and realize the cascade, continuous, and complete drug release after enzymatic decomposition, which not only aids with high tissue affinity to prolong the resistance time but also improves the comfort of use. The preclinical study reveals that contributed by the above actions, such buccal tablets mitigate inflammation, promote endothelium proliferation and migration, and accelerate wound healing for repressing chemotherapy‐originated intractable OM with positive oral microenvironment and shorter recovery time, thus holding high potentials in clinical translation.
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