Unleashing Novel Therapeutic Strategies for Dry Eye: Targeting ROS and the cGAS‐STING Signaling Pathway with Tetrahedral Framework Nucleic Acids

Dry eye affects majority of the global population, causing significant discomfort or even visual impairment, of which inflammation plays a crucial role in the deterioration process. This highlights the need for effective and safe anti‐inflammatory treatments to achieve satisfactory therapeutic outcomes. This study focuses on the potential of tetrahedral framework nucleic acids (tFNA), a self‐assembled nucleic acid material, as a simple and rapid treatment for oxidative stress and inflammation‐induced disorders associated with dry eye. Mechanistically, tFNA is found to effectively alleviate dry eye damage by promoting corneal epithelial healing, restoring goblet cell function, and facilitating tear secretion recovery. Through RNA‐seq analysis, it is observed that tFNA treatment normalizes the expression levels of most genes. Further exploration of the mechanism reveals that tFNA reduces excessive production of reactive oxygen species and modulates the inflammatory microenvironment, especially through cGAS‐STING pathway thereby levels of inflammatory cytokines, including MMP9 and IL‐6, are reduced. Additionally, tFNA demonstrates excellent safety performance without causing damage to the eye. Importantly, this study represents a successful application of nanophase materials with nucleic acid biological features for the effective treatment of dry eye, highlighting the potential clinical use of tFNA in the treatment of dry eye. In dry eye, inflammation, hyperosmolarity, cell apoptosis, and tear film decline worsen the condition. Treatment with tetrahedral framework nucleic acids (tFNA) disrupts this cycle. tFNA, engulfed by corneal epithelial cells, inhibit ROS, and suppress the cGAS‐STING signaling pathway. This decreases NF‐κB pathway activation and reduces inflammatory cytokines like MMP‐9 and IL‐6, promoting ocular surface restoration and stabilization.