Multi‐Omics‐Guided Design and Safety Engineering of Nucleic Acid Therapeutics: From Molecular Perturbation to Predictive Toxicology and Precision Translation
Aug 2026· Chemical Biology and Drug Design· Vol 108· 0 citations· 174 references
Medicine
TL;DR
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 is offered.
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.
This review summarizes current and emerging model‐informed drug development applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs.
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A rapidly growing class of medications called RNA therapeutics could transform indi-vidualized treatment and target "undruggable" areas. The different forms of RNA-based treat-ments, such as messenger RNAs (mRNAs), small interfering RNAs (siRNAs), and circular RNAs (circRNAs), are discussed in this paper along with their significance in gene regulation and the treatment of disease. Stability and efficient distribution to target cells are major challeng-es for RNA molecules. Hydrogels, dendrimers, and lipid nanoparticles are being developed to improve RNA therapy pharmacokinetics and cellular absorption. More accurate and efficient therapies are also being made possible by breakthroughs in self-amplifying RNA (saRNA) tech-nology and the application of artificial intelligence in RNA delivery design. The review also dis-cusses RNA modifications and synthetic biology in pharmaceutical design. Although good data from preclinical and clinical trials demonstrate the potential of RNA-based therapeutics, further research is necessary to tackle translational difficulties and improve delivery mechanisms for therapeutic usage. RNA treatments may revolutionize medical research by treating cancer and genetic defects.
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The principles that shape cardiovascular ASO candidate development are discussed, with emphasis on mechanism selection, chemical design, and exposure feasibility, and sequence optimization with exposure-informed target qualification and therapeutic-index engineering throughout ASO candidate selection.
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Small interfering RNAs (siRNAs) are programmable nucleic acids that play key roles in chemical biology and can selectively silence disease-associated genes through RNA interference (RNAi). These programmable nucleic acids have emerged as a powerful class of medicines and chemical biology tools that can rewire tumor-immune signaling, target immunosuppressive genes, stimulate immune responses, and boost the immune system against immune-mediated diseases. Recent success in the rapid synthesis and applications of siRNA highlights the potential of this technology to address previously “undruggable” targets across a range of genetic, metabolic, and oncologic diseases. Despite the potential of these siRNA-based therapies, including those used in cancer immunotherapy, challenges such as off-target effects during delivery, chemical degradation of siRNA in the body, and immunogenicity limit their efficacy. This review provides a comprehensive overview of the chemical biology and chemical modifications inherent to the design of robust siRNA therapies; the nucleic acid structure–function relationships that dictate the cellular mechanisms underlying siRNA-mediated gene silencing and efficacy; and the current clinical landscape and safety of approved siRNA therapeutics for immunotherapy. We examine the growing role of computationally guided design strategies and emerging machine-learning-based methods in optimizing siRNA chemical design, and outline how recent advances in siRNA chemical modification are expected to improve targeted gene modulation in the clinic. Additionally, we examine the role of delivery systems in enhancing siRNA potency, with an emphasis on tumor-targeted and tissue-specific approaches, as well as emerging combination therapies integrating siRNA with chemotherapy, immune checkpoint blockade, siRNA and mRNA co-delivery, and prodrug activation.
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Cervical cancer pharmacotherapy is significantly limited by physiological and cellular barriers that restrict drug access to therapeutic targets, resulting in suboptimal biodistribution, systemic toxicity, and the emergence of drug resistance. This review provides a mechanistic and biopharmaceutics-centered analysis of how advanced drug delivery systems are being engineered to overcome these limitations. We critically examine the role of nanocarriers, including lipid-based vesicles, polymeric nanoparticles, and inorganic hybrid systems, in modulating absorption, distribution, and tumor-targeting efficiency, with emphasis on their physicochemical properties and interaction with biological barriers such as the tumor microenvironment and cellular uptake pathways. In parallel, we analyze nucleic acid-based therapeutics (CRISPR/Cas systems, miRNA, and antisense oligonucleotides) from a pharmaceutical sciences perspective, focusing on delivery constraints, stability, intracellular trafficking, and their ability to modulate pharmacological response and drug resistance mechanisms. The review also discusses the integration of immunomodulatory strategies within nanodelivery platforms as a means to alter disease-related biological barriers and improve therapeutic index. Finally, we explore the emerging role of AI-assisted models in optimizing formulation design, predicting pharmacokinetic behavior, and supporting precision dosing strategies in drug development workflows. By integrating drug delivery engineering, molecular biopharmaceutics, and computational optimization, this work outlines a translational framework for overcoming key barriers in pharmaceutical intervention design for oncology applications.
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