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However, novel chemistries are still required to discover modifications which improve their druggable properties. For in vitro studies, thermal duplex stability, resistance to enzymatic degradation and gymnotic cellular activity are important, and biodistribution, toxicology and potency must be optimised for clinical progression. We investigate the combination of locked nucleic acids (LNA) and charge neutral backbones in chimeric ASOs containing 2\u2032\u2010O\u2010methyl sugars and phosphorothioate backbones by evaluating their physical and biological properties. Backbones investigated are LNA\u2010amide, LNA\u2010carbamate, LNA\u2010alkoxyamide, and LNA\u2010sulfamate. Molecular dynamics simulations of these LNA\u2010charge neutral backbones were conducted to explore the structural features which determine the experimentally observed thermal duplex stability and conformation. The LNA\u2010sulfamate linkage is of particular interest, forming very stable duplexes with its RNA target and having comparable gymnotic activity to the previously investigated LNA\u2010amide, while being synthetically more accessible. Together, our studies indicate that a multi\u2010faceted approach to expanding the ASO chemical space, using a combination of computational and experimental methods, can build structure\u2010activity relationships and discover novel promising backbones for future therapeutic use.<\/jats:p>","DOI":"10.1002\/anie.202511386","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T06:32:51Z","timestamp":1758522771000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis, Biological Activity, and Molecular Dynamics Simulations of LNA\u2010Charge Neutral Linkages for Enhanced Splice\u2010Switching Antisense Oligonucleotides"],"prefix":"10.1002","volume":"64","author":[{"given":"Alice","family":"Kennett","sequence":"first","affiliation":[{"name":"Department of Chemistry University of Oxford Chemistry Research Laboratory  12 Mansfield Road Oxford OX1 3TA 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