Abstract During the development of oral squamous cell carcinoma (OSCC), multiple danger signals can initiate chronic oral mucosal inflammation, which then gives rise to precancerous and cancerous lesions. Modulation of immune homeostasis is essential to intercept inflammation-driven OSCC. In this study, we aimed to identify key inflammatory danger signals involved in precancerous oral mucosal inflammation and to develop a locally applicable immunomodulatory strategy to prevent this precancerous inflammation. We first identified saliva cell-free DNA (cfDNA) levels and cfDNA-induced TLR9 activation were linked to OSCC development and progression. Hypothesizing that removing cfDNA would be beneficial for OSCC prevention, we created a cationic nanoparticles-enabled mouthwash that regulates precancerous inflammation via removing negatively charged cfDNA. Both cationic nanoparticles and polymers inhibited the in vitro cellular proinflammatory response induced by plasma from OSCC patients and suppressed OSCC patient plasma-induced tumor cell migration and stemness. In the precancerous mouse model, cationic nanoparticles-enabled mouthwash alleviated oral mucosal inflammation via inhibiting TLR9 activation. Overall, our study highlights the role of cfDNA in OSCC progression and the potential of cationic nanoparticle-enabled mouthwash for treating OSCC-related precancerous oral mucosal inflammation.
Du et al. (Mon,) studied this question.