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However, their clinical application is severely limited by their low serum stability in complex physiological environments. In this work, a precise molecular programming strategy is explored to prepare glyconucleic acid aptamers (GNAAs) with high serum stability. Four glyconucleic acid modules compatible with commercial solid\u2010phase synthesis are designed and synthesized. Through precise molecular design, the accurate modification of four different carbohydrate ligands at specific sites of DNA aptamers is achieved. It is demonstrated that glycosylation modification can significantly increase DNA aptamers\u2019 serum stability while maintaining their structures and high affinity. The stabilization effect is superior to that of currently commonly used commercial chemical modifications. Moreover, it is confirmed that this approach displays insignificant effects on the DNA aptamers\u2019 tumor\u2010targeting ability and metabolism in vivo. This method offers a simple, economical, and efficient strategy for precise glycosylation modification of nucleic acids. This allows to prepare glycosyl functional nucleic acids with high serum stability, which can expand the application scope of functional nucleic acids and promote the practical transformation of functional nucleic acids.<\/jats:p>","DOI":"10.1002\/advs.202408168","type":"journal-article","created":{"date-parts":[[2024,12,4]],"date-time":"2024-12-04T09:50:42Z","timestamp":1733305842000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Molecular Programming Design of Glyconucleic Acid Aptamer with High Stability"],"prefix":"10.1002","volume":"12","author":[{"given":"Yongqi","family":"Han","sequence":"first","affiliation":[{"name":"Institute of Molecular Medicine (IMM) Renji Hospital State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine  Shanghai 200240 China"},{"name":"College of Chemistry and Materials Science Shanghai Normal University  Shanghai 200234 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine (IMM) Renji Hospital State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Liang","family":"Bao","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine (IMM) Renji Hospital State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine  Shanghai 200240 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine (IMM) Renji Hospital State Key Laboratory of Oncogenes and Related Genes Shanghai Jiao Tong University School of Medicine  Shanghai 200240 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