Evaluating Off-Targets of siRNA Drugs

siRNA holds great promise as a therapeutic modality due to its high specificity, developability, and sustained efficacy. However, its application is challenged by sequence-dependent off-target effects, which can compromise both safety and therapeutic effectiveness. A critical step in siRNA drug development is the rigorous evaluation and mitigation of these off-target effects.

Off-target assessment can be influenced by multiple factors, including siRNA sequence design, chemical modifications, delivery strategies, and species- and cell type-specific responses. At OTS 2025, WuXi AppTec presented a poster describing a study that systematically investigated the impact of these factors. The authors highlight the use of comprehensive transcriptomic profiling to evaluate off-target effects across diverse experimental conditions and, based on these results, offer recommendations to help develop safer and more effective oligonucleotide therapies.