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However, the efficacy of current protein degradation methods still needs to be improved to address the complex mechanisms underlying diseases. Herein, a LYTAC Plus hydrogel engineered is proposed by nucleic acid self\u2010assembly, which integrates a gene silencing motif into a LYTAC construct to enhance its therapeutic potential. As a proof\u2010of\u2010concept study, vascular endothelial growth factor receptor (VEGFR)\u2010binding peptides and mannose\u20106 phosphate (M6P) moieties into a self\u2010assembled nucleic acid hydrogel are introduced, enabling its LYTAC capability. Small interference RNAs (siRNAs) is then employed that target the angiopoietin\u20102 (ANG\u20102) gene as cross\u2010linkers for hydrogel formation, giving the final LYTAC Plus hydrogel gene silencing ability. With dual functionalities, the LYTAC Plus hydrogel demonstrated effectiveness in simultaneously reducing the levels of VEGFR\u20102 and ANG\u20102 both in vitro and in vivo, as well as in improving therapeutic outcomes in treating neovascular age\u2010related macular degeneration\u00a0in a mouse model. As a general material platform, the LYTAC Plus hydrogel may possess great potential for the treatment of various diseases and warrant further investigation.<\/jats:p>","DOI":"10.1002\/advs.202306248","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T05:14:40Z","timestamp":1705900480000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Nucleic Acid\u2010Based LYTAC Plus Platform to Simultaneously Mediate Disease\u2010Driven Protein Downregulation"],"prefix":"10.1002","volume":"11","author":[{"given":"Yangyang","family":"Huang","sequence":"first","affiliation":[{"name":"School of Chemistry and Chemical Engineering Frontiers Science Center for Transformative Molecules Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs Shanghai Jiao Tong University  Shanghai 200240 P. R. 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