Ferumoxytol nanoparticles stabilize stannous fluoride for synergistic biofilm disruption and tooth-decay prevention

Human dental caries (tooth decay) is the most prevalent disease caused by microbial biofilms affecting nearly half of the global population. Current treatments are insufficient in severe cases when pathogenic dental biofilms rapidly accumulate and cause rampant enamel demineralization. Fluoride, the mainstay anticaries agent, can protect the enamel but is ineffective against biofilms. Recently, FDA-approved ferumoxytol (Fer) nanoparticles have been shown to disrupt caries-causing biofilms via catalytic activation of hydrogen peroxide. However, Fer is incapable of preventing demineralization. Here, we find notable synergy when Fer is combined with stannous fluoride (SnF2), markedly inhibiting both biofilm accumulation and enamel damage more effectively than either alone. Unexpectedly, our data show that SnF2 enhances the catalytic activity of Fer, significantly increasing ROS generation and antibiofilm activity. We also discover that the stability and delivery of SnF2 is enhanced when mixed with Fer. Further analysis reveals that Sn2+ is bound by carboxylate groups in the carboxymethyl-dextran coating of Fer, indicating co-assembly. Notably, Fer in combination with SnF2 is exceptionally effective in controlling dental caries in vivo, preventing enamel demineralization and cavitation altogether without adverse effects on the surrounding host tissues or oral microbiome. The efficacy of SnF2 is also enhanced when combined with Fer, showing comparable therapeutic effects at four times lower fluoride concentration. Enamel ultrastructure examination shows that fluoride, iron, and tin are detected in the outer layers of the enamel, suggesting co-delivery and chemical incorporation onto the tooth surface. Overall, our results reveal an unexpected therapeutic synergism using approved agents that complementary target the biological and physicochemical traits of a widespread oral disease while providing a fluoride delivery alternative.