A novel drug delivery system for the treatment of oral cancer was developed using a facile polydopamine (PDA)-based surface modification and a binding mechanism linking folic acid-targeting ligands. The system was able to achieve the following objectives: loading of chemotherapeutic agents, active targeting, pH responsiveness, and prolongedin vivoblood circulation. DOX-loaded polymeric nanoparticles (DOX/H20-PLA@PDA NPs) were functionalized with amino-poly (ethylene glycol)-folic acid (H2N-PEG-FA) after coating them with PDA to form the targeting combination, DOX/H20-PLA@PDA-PEG-FA NPs. The novel NPs exhibited drug delivery characteristics similar to DOX/H20-PLA@ PDA NPs. Meanwhile, the incorporated H2N-PEG-FA contributed to active targeting, as illustrated in cellular uptake assays and animal studies.In vitrocytotoxicity andin vivoanti-tumor studies have shown that the novel nanoplatforms exhibit extremely effective therapeutic effects. In conclusion, the multifunctional PDA-modified H20-PLA@PDA-PEG-FA NPs offer a promising chemotherapeutic strategy to improve the treatment of oral cancer.