Administration of drug via the buccal route has attracted much attention in recent years. However, developing system with satisfactory adhesion in wet conditions and drug bioavailability still remains a challenge. Here, we propose a mussel inspired mucoadhesive film. Ex vivo porcine and in vivo rat models show that the film can achieve strong adhesion with wet buccal tissues. We also demonstrate that the film exhibits tunable mucoadhesion strength and erosion rate. The adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Then, polydopamine (PDA) modified nanoparticles (NPs) are incorporated into the film and the PDA NPs loaded films show superior advantages to transport across multiple barriers of buccal mucosa with improved drug bioavailability and therapeutic efficacy in oral mucositis models. We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.