Dental caries represents a multifactorial disease that results from interactions among dental biofilms, the oral environment, and tooth structure. Mounting reports in the literature demonstrated that fluoride could decrease enamel demineralization and enhance enamel remineralization, and at sufficient concentrations, could inhibit acid production by cariogenic bacteria. Fluoride is the cornerstone for dental caries prevention and remains its first line of defense. Yet despite the extensive use of fluoride in dentistry for decades, dental caries remains a serious public health problem worldwide. Limitations of current fluoride delivery technologies include low penetration of delivered fluoride into sub-surface areas and short-term retention of delivered fluoride on teeth, which prevent the full utilization of fluoride. However, few advancements in F technologies have been made in past decades to overcome these limitations. We were inspired by reports that fluorine nonthermal plasmas (FNTPs) generated from F-containing feed gases could produce free F atoms (F- ions and F free radicals) and that FNTPs have been used to synthesize various metal fluorides. Our pioneering work in this area has demonstrated that FNTPs can deliver fluoride into tooth enamel and enhance its remineralization using an in vitro pH cycling experiment. Moreover, our previous in vitro work demonstrated that both argon (Ar) and Ar/O2 nonthermal plasmas (NTPs) efficiently decrease S. mutans cells and S. mutans biofilm formation. Our in vivo study in female Sprague–Dawley rats showed that rat molars treated with 2-minute Ar/O2 plasmas exhibited less decayed tooth surfaces 6 months after the plasma treatment, 62.5% less on the upper molars and 31.6% less on the lower molars relative to untreated molars. In this application, we propose to generate biocompatible FNTPs and investigate their efficiencies on tooth enamel remineralization, fluoride delivery into enamel, and inhibition of dental biofilm recovery with the ultimate goal of developing FNTPs for control of dental caries. Our central hypothesis is that biocompatible FNTPs generated from a plasma feed gas comprised of argon (Ar) gas and a nontoxic and nonirritating F-containing gaseous compound will have the dual effects of enhancing remineralization via effective fluoridation and inhibiting biofilm recovery. Two specific aims are designed to test this hypothesis. Specific Aim 1, to generate biocompatible FNTPs with desirable fluoride delivery capabilities, and Specific Aim 2, to assess the effect and efficiency of FNTP treatment on enhanced remineralization of enamel, fluoride delivery into enamel, and inhibition of dental biofilm recovery in vitro. This proposed research project will not only contribute to our fundamental knowledge of FNTP generation and their interaction with tooth enamel and dental biofilms, but also facilitate the development of FNTPs as an innovative approach for prevention and early treatment of dental...