Small oligonucleotides (antisense, siRNA, aptamers) offer great therapeutic promise as new platforms for treating disease. After years of limited success, advances in modifying oligonucleotides with non-native chemistries and improvements in delivery systems have afforded some clinical successes, leading to a number of approvals by regulatory agencies. Despite this progress, experimental strategies for structural characterization of oligonucleotide drugs have not been established which meet the typical rigors in drug development, quality control and assurance. To address this gap, research will focus on development of robust approaches for structural characterization of oligonucleotide therapeutic drug platforms, with an emphasis on methods using high resolution nuclear magnetic resonance (NMR) spectroscopy. While NMR has been rigorously developed for protein-based therapeutics, there remains an open question on appropriate implementation to therapeutic oligonucleotides. Using NMR, atomic level analysis will be used to evaluate molecular stability from studies such as forced degradation, and appropriate chemometric approaches will be applied for evaluation of structural fingerprints. In addition, methods to determine impact of a delivery system (lipid nanoparticles, GalNac, etc.) on oligonucleotide structure will also be investigated.