Project Summary Antibiotics and anti-inflammatory agents administered separately attack pathogens or the destructive inflammatory response. Both agents are non-specific and have off-target effects that are not therapeutically optimal. By engineering the body's own proteins to be expressed or over-expressed, we propose to develop a dual-armed therapeutic, controlling levels of bacteria and fungi and simultaneously minimizing the tissue destruction that accompanies the attendant inflammation during infection. Periodontitis is an excellent first disease target for the proposed dual therapy. Periodontitis results from microbial dysbiosis and the tissue pathology is largely attributed to the resulting inflammation. Using our well-characterized experimental periodontitis model in mice, we hypothesize that topical gingival application of food-safe, packaged mRNA encoding calprotectin (complexed S100A8 and S100A9; S100A8/A9) will attenuate the microbial insult and mRNA encoding 15'-lipoxygenase will mitigate the inflammatory response. To test our hypothesis, we will: 1. compare each mRNA species administered alone for impact on the local microbiome, inflammatory cell infiltrate, and alveolar bone loss in the periodontitis model; and 2. characterize the synergistic therapeutic response to dual therapy when both mRNA species are administered together. To learn how administration of the proposed therapeutic mRNAs might work, levels of endogenous S100A8/A9 and endogenous lipoxin will be determined and augmentation of the respective proteins will be confirmed. The therapeutic benefit of the dual mRNA transfection technology will be compared to each alone in attenuating the dysbiotic microbiome, inflammatory cell infiltrate, and alveolar bone loss. By expressing the native proteins of the mucosal epithelium, we propose that this auto-therapy will reduce signs of periodontitis and serve as guidance for development of similar therapeutics for other mucosal infections.