Multi‐Omics‐Guided Design and Safety Engineering of Nucleic Acid Therapeutics: From Molecular Perturbation to Predictive Toxicology and Precision Translation

Abstract

Nucleic Acid Therapeutics (NATs), including Antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and messenger RNAs (mRNAs), are a rapidly developing class of therapeutics capable of specifically regulating previously considered undruggable and inaccessible genes and pathways for modification by small molecules and antibodies. Despite promising results, the utilization of NATs in clinical practice is complicated by the potential off‐target effects, such as activation of the immune response and organ‐specific toxicity, which cannot be effectively predicted based solely on primary structure, chemotype descriptors, or off‐target effects predictors developed in silico. A combination of multiple omics technologies, including proteomics/metabolomics/single‐cell transcriptomics, helps researchers elucidate the interaction of drug compounds with biological targets. This allows for the detection of changes not only at the pathway and cellular level but also early signs of toxicity in parallel. Thus, in this context, this review offers a mechanistic view on the use of multi‐omics strategies for the investigation of NATs‐induced biological effects to analyze the mechanism of action of chemically modified ASOs, siRNAs and mRNA conjugates. The review also discusses case studies in which multi‐omics data have been used to improve therapeutic development. By examining individual layers of molecules separately, a more holistic understanding of treatment mechanisms can be achieved, which is helpful for the discovery of biomarkers and the development of next‐generation nucleic acid drugs.