Development of Biocompatible Fatty Acid-Based Ionic Liquids for the Effective Topical Treatment of Periodontitis

Periodontitis is a widespread chronic inflammatory disease characterized by the progressive destruction of tooth-supporting structures, ultimately causing tooth loss and impaired quality of life. Pathogenic microorganisms residing in the periodontal pockets are involved in disease progression. While antibiotics are widely used, the global rise of antimicrobial resistance underscores the urgent need for alternative treatments. Ionic liquids (ILs), which are salts composed of cations and anions that remain liquid at or near room temperature, have emerged as promising alternative antimicrobial agents. Their highly tunable nature, achieved by modifying ion combinations, allows for the development of ILs with potent antimicrobial activity, such as choline and geranate (CAGE). However, they can be cytotoxic at concentrations near the therapeutic effective dose, thereby limiting their clinical application. Moreover, recent microbiology advances highlight the need for agents that can effectively target polymicrobial biofilms, which exhibit greater resistance to treatment than their planktonic counterparts. Therefore, this study aimed to optimize IL properties based on the CAGE framework by modifying their ionic composition to enhance their antibiofilm efficacy while improving their biocompatibility. Fatty acids, commonly found in food, cosmetics, and skincare products, were selected as alternative anion donors. Fatty acid-based ILs, particularly choline and oleic acid ([Cho]-[Ole]) and choline and linoleic acid ([Cho]-[Lin]), exhibited strong antimicrobial and antibiofilm efficacy at markedly lower concentrations. In a mouse model, topical application of these ILs significantly reduced subgingival infection. Furthermore, these new ILs demonstrated broader safety margins and caused no tissue irritation even after repeated applications. Therefore, rational ion pairing with fatty acid anions may enhance both ILs' safety and efficacy, making fatty acid-based ILs promising candidates as next-generation topical agents for periodontal therapy.