ABSTRACT Peri-implant (PI) diseases, mucositis and peri-implantitis, eventually affect ~25-50% of dental implants after placement, resulting in soft tissue and bone destruction. Current treatments target dysbiosis of the oral microbiome (mature plaque) on the implant surface as the primary etiological factor of PI diseases. Conventional treatment options include mechanical and/or chemical debridement, laser treatment, ultrasonic scaling, and implantoplasty. Despite improvements in biofilm removal, decontamination may inadvertently worsen PI disease prognosis by damaging the implant surface, generating ions/particles that exacerbate the host inflammatory immune response. Furthermore, these detoxification protocols do not address the chronic inflammatory environment sustaining PI host tissue destruction. The lack of controlled immunomodulation at the PI diseased site can hinder re-integration of host tissue with a previously biofilm-contaminated implant surface. Thus, the ideal PI disease treatment should (i) eliminate infection, (ii) preserve Ti surface condition, and (iii) possess immunomodulatory activity conducive towards healing at the tissue-implant interface. Previously, our research group demonstrated the use of dicationic imidazolium-based ionic liquids (IonLs) with amino acid-based anionic moieties as multifunctional coatings on dental implants. In particular, we showed that IonL functionalized with phenylalanine (IonL-Phe) formed stable coatings on Ti, imparting host cell compatibility, antimicrobial activity, anti-corrosive ability, and lubrication in vitro in addition to in vivo biocompatibility and oral osseointegration in a rat model. During in vivo assessment, IonL-Phe-coated Ti implants also differentially upregulated inflammation resolution and bone matrix marker genes versus non-coated implants. This observed immunomodulatory activity motivated evaluation of IonL-Phe application as a multifunctional therapeutic agent for PI disease treatment. To assess the potential of IonL-Phe in combination with detoxification regimens to promote implant re-integration, the following aims are proposed. In Aim 1, a standard method for application of IonL-Phe will be determined based on release kinetic studies and its effect on detoxified Ti surface properties. In Aim 2, an in vitro evaluation of IonL-Phe application on plasma protein deposition and subsequent effect on mammalian cell growth under bacterial challenge or multispecies bacterial adhesion on detoxified Ti will be performed. In Aim 3, the in vivo impact of IonL-Phe application on protein layer formation, host tissue re-integration with Ti implant surface, and oral microbiome composition will be assessed after induction of PI diseases in a rat model. The proposed study will address the current clinical gap in treatment of PI diseases by elucidating the ability of IonL to (i) protect the implant surface during the acute healing phase, (ii) mitigate regrowth of bacterial biofilm, and (ii...