ABSTRACT Dental caries remains an unresolved disease affecting more than 2.3 billion people worldwide. It disproportionally afflicts impoverished families and medically compromised populations, including those with comorbidities such as iron-deficiency anemia. Current approaches are insufficient for susceptible populations, where biofilms rapidly accumulate under sugar-rich diets and poor oral hygiene leading to onset of dental caries that cannot be effectively controlled, requiring new antibiofilm approaches. Fluoride, the anticaries mainstay, promotes remineralization and reduces tooth enamel demineralization, but is ineffective against biofilms. Conversely, current antimicrobials are restricted to broad-spectrum agents that can disrupt oral microbiota diversity while lacking efficacy against dental caries. Thus, an alternative approach is needed to address the limitations of current treatments and help control dental caries under pathogenic conditions. A major challenge is the rapid establishment of intractable microbial biofilms in susceptible individuals. In cariogenic biofilms, bacterial cells are enmeshed in an exopolysaccharides (EPS) matrix, forming highly organized and protected biostructures that create localized acidic microenvironments. These low pH niches further induce cariogenic bacteria growth, ensuring biofilm build-up and acid dissolution of tooth enamel. To overcome these challenges, new antibiofilm strategies are needed to precisely target the biofilm properties and the acidogenic environment, and at the same time, prevent enamel acid-demineralization. In the previous funding period, we studied the potential of catalytic (peroxidase mimics) iron oxide nanoparticles (IONP) for controlled, acidic pH-dependent activation of hydrogen peroxide as a novel antibiofilm and anticaries treatment. We found that this approach potently disrupted cariogenic biofilms and blocked apatite acid dissolution, significantly reducing dental caries in rodent models. Furthermore, we discovered that coating IONP with dextran enhanced targeting specificity by improving retention and incorporation into biofilm, while deterring binding to cellular and soft-tissue surfaces, providing a selective biofilm-targeting approach. In vivo studies revealed that dextran coated IONP were highly effective against caries development without affecting gingival/mucosal tissues and oral microbiome diversity, confirming therapeutic precision. These findings were further confirmed using ferumoxytol, an FDA-approved IONP used for iron deficiency therapy, that has similar size and dextran-coating to those made in-house. Recently, we received an IND exemption for repurposing ferumoxytol for topical treatment in human in situ model studies. This proposal is to further develop and understand catalytic nanoparticle technology for effective treatment of cariogenic biofilms and prevention of dental caries using the ferumoxytol FDA approved IONP as a nanocarrier.