Abstract Vulcan Biologics is developing a platform that harnesses the power of synthetic biology to enable persistent and stable modulation of the oral microbiome for the prevention of dental caries. Caries are characterized by the acidification and degradation of tooth enamel when dietary sugars come into contact with dental biofilms (plaque). Dental caries is the most prevalent chronic disease in humans, affecting 42% of children, 59% of adolescents, and 92% of adults in the U.S. It can be accompanied by serious comorbidities and complications, including pain, abscesses, dental sepsis, and even death. Caries also contribute to diminished quality of life and account for an estimated $5.4 billion in lost productivity each year. Current methods to prevent caries, including brushing/flossing and fluoride applications, have done little to reduce the overall prevalence of caries in the population in the last decade, thus necessitating the development of more effective measures. There is an increasing awareness of the role of the oral microbiome in dental caries pathogenesis. Streptococcus mutans is a naturally occurring member of the oral microbiota and the principal etiological agent of dental decay in humans. Vulcan Biologics proposes a tripartite approach for the persistent and stable reprogramming of the oral microbiome to reduce or eliminate the prevalence of S. mutans. This approach is based on combining the application of bacteriophages—viruses that exclusively target bacteria but do not affect eukaryotic cells—with selected bacteria providing a probiotic effect and nutrients (prebiotics) that are specific to the protective probiotic bacteria. This decolonization/recolonization (Decon-Recon) strategy has the potential to succeed where previous attempts to provide effective and enduring modulation of the microbiome have failed, namely in overcoming the resistance of established microbial communities to the permanent engraftment of newcomers. To demonstrate the feasibility of this approach, in this Phase I project, Vulcan Biologics will: 1) establish and characterize bacterial and phage libraries, including isolating novel virulent phages from saliva samples and analyzing their host ranges; 2) engineer virulent phages with antimicrobial peptides and biofilm-degrading enzymes to improve S. mutans killing ability; and 3) establish a biofilm model and assess S. mutans reduction resulting from phage treatment alone, probiotic treatment alone, or their combination. This will test the effectiveness of the first two steps in our 3-part approach and pave the way for Phase II work to evaluate the efficacy upon integration of all 3 steps (i.e., providing a prebiotic) and in a rat model. Ultimately, this approach promises to provide a long-term and persistent method to prevent dental caries.