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Yet, current treatments for moderate\u2010to\u2010severe 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 \u201cBarrier to Target,\u201d an siRNA\u2010embedded nucleic acid hydrogel modified with a mucin\u20101 (MUC1) aptamer is developed to actively target the ocular surface for DED treatment. Upon distillation, the adhesive feature and aptamer\u2010mucin 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\u2010B inhibitor, zeta (NFKBIZ) gene can effectively silence the target gene expression, initiating a cascade of inflammation\u2010related 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\u2010dependent nature of siRNA drugs, our targeting hydrogel may serve as a general platform for treating various ocular surface diseases.<\/jats:p>","DOI":"10.1002\/exp.20240461","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T19:59:13Z","timestamp":1784145553000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Ocular Surface\u2010Targeting Nucleic Acid Hydrogel for Efficient Dry Eye Disease Treatment"],"prefix":"10.1002","volume":"6","author":[{"given":"Yuhe","family":"Liu","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering State Key Laboratory of Synergistic Chem\u2010Bio Synthesis Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai P. R. 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