An Ocular Surface-Targeting Nucleic Acid Hydrogel for Efficient Dry Eye Disease Treatment.

Dry eye disease (DED) is a prevalent disorder affecting millions worldwide, fueled by both the aging population and extensive use of electronic devices. Yet, current treatments for moderate-to-severe DED fail to fully meet the clinical needs due to the lack of effective therapeutics and delivery systems for topical application. Based on the concept of "Barrier to Target," an siRNA-embedded nucleic acid hydrogel modified with a mucin-1 (MUC1) aptamer is developed to actively target the ocular surface for DED treatment. Upon distillation, the adhesive feature and aptamer-mucin recognition of the hydrogel enhance its retention on the ocular surface. Over time, tear dilution and the shear force of blinking lead the hydrogel to degrade into nanosized gel particles, facilitating drug uptake by corneal cells. Subsequently, the embedded siRNA targeting the nuclear factor of kappa-B inhibitor, zeta (NFKBIZ) gene can effectively silence the target gene expression, initiating a cascade of inflammation-related gene suppression. This comprehensive gene regulation effectively reshapes the inflammatory corneal environment to a normal state and alleviates the severity of DED in a mouse model. With the sequence-dependent nature of siRNA drugs, our targeting hydrogel may serve as a general platform for treating various ocular surface diseases.