Organoids and organ-on-a-chip platforms for advancing oligonucleotide drug development

Oligonucleotide therapeutics (ONTs) enable precise modulation of gene expression and RNA function through diverse sequence- and structure-dependent mechanisms but face translational challenges in conventional animal models, particularly for human-specific biology. This review focuses on organoids and organ-on-a-chip platforms as emerging human-relevant models within the broader framework of new approach methodologies for oligonucleotide drug development. We summarize major oligonucleotide modalities and biological barriers to cellular uptake and intracellular trafficking, emphasizing hepatic delivery and extrahepatic applications. Representative studies illustrate their use in assessing target engagement, RNA modulation, pharmacological response and safety. We further discuss regulatory considerations, context of use and current limitations. Further development of these models is expected to enhance translational relevance and support the development of ONTs.