The oral cavity is a unique complex ecosystem colonized with huge numbers of microorganism species. Oral cavities are closely associated with oral health and sequentially with systemic health. Many factors might cause the shift of composition of oral microbiota, thus leading to the dysbiosis of oral micro-environment and oral infectious diseases. Local therapies and dental hygiene procedures are the main kinds of treatment. Currently, oral drug delivery systems (DDS) have drawn great attention, and are considered as important adjuvant therapy for oral infectious diseases. DDS are devices that could transport and release the therapeutic drugs or bioactive agents to a certain site and a certain rate in vivo. They could significantly increase the therapeutic effect and reduce the side effect compared with traditional medicine. In the review, emerging recent applications of DDS in the treatment for oral infectious diseases have been summarized, including dental caries, periodontitis, peri-implantitis and oral candidiasis. Furthermore, oral stimuli-responsive DDS, also known as "smart" DDS, have been reported recently, which could react to oral environment and provide more accurate drug delivery or release. In this article, oral smart DDS have also been reviewed. The limits have been discussed, and the research potential demonstrates good prospects.Molecules 2020, 25, 516 2 of 29 problems. For example, systemic antibiotics such as tetracycline, beta-lactam antibiotics, nitroimidazoles have been used, especially in cases of periodontal diseases and peri-implantitis [12]. However, systemic antibiotics could cause problems like drug resistance, dysbacteriosis, and systemic side effects [13,14]. The antibacterial effect is also limited as very little could arrive at the oral lesion area after systemic circulation [15][16][17]. Fluoride in drinking water has been used for the prevention of dental caries but might cause excessive intake, leading to fluorosis [18]. Therefore, local drug therapy is now more considered for oral infectious diseases [19,20]. However, the conventional forms of local therapy, like drug suspension or rinse of anti-infection agents, could be easily washed off and thus could not last long in the oral cavity. Complex local lesions like deep periodontal pockets and teeth fissure are also difficult to reach. In order to improve the effect of prophylaxis and treatment, more precise targeting therapy is quite essential [21,22]. Therefore, drug delivery systems have drawn great attention in recent decades in oral infectious diseases. Drug delivery systems (DDS) are devices that can transport and release the therapeutic agents or bioactive substances to certain sites at certain rates in vivo [23,24], usually composed of the carriers and associated therapeutics [25]. They have been widely explored in biomedical research. With local drug administration and controlled drug release, DDS could provide higher curative efficiency and fewer side effects [23,26,27]. With all these advantages, DDS has been reported w...