The toxicological landscape of short nucleic acid therapeutics: a short review of toxicity mechanisms, clinical translation, and regulatory frameworks

RNA-targeting therapies, particularly antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), represent a crucial advancement in molecular medicine. This review examines the therapeutic potential and inherent challenges of these modalities, highlighting their distinct advantages, design flexibility, a broad range of addressable targets, and high specificity. The critical role of chemical modifications in ASO and siRNA design is discussed, emphasizing the necessity of advanced computational tools for toxicity prediction. While numerous therapies have received regulatory approval, their clinical translation has revealed a landscape of modality-specific adverse events. Obstacles encountered in clinical trials, such as delivery difficulties and off-target effects, are investigated, with a focus on differentiating the safety profiles of distinct therapeutic classes like ASO gapmers, splice-switching oligonucleotides (SSOs), and siRNAs. Furthermore, it explores the translational relevance of preclinical models by examining species-specific toxicological differences and discusses the evolving regulatory frameworks designed to guide their development. The integration of computational methods, enhanced chemical modifications, and innovative delivery strategies is clearly paving the way for more efficacious and safer therapeutics. As our understanding of RNA biology deepens, a corresponding evolution in safety science and regulatory oversight will be paramount for realizing the full clinical potential of RNA based therapeutic modalities.