Advances in antisense technology for cardiovascular drug discovery: from gene silencing to therapeutics.

Pharmacokinetic/Pharmacodynamic Translation and Model‐Informed Drug Development for Oligonucleotide Therapeutics

Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) have emerged as clinically validated therapeutic modalities, with approvals and late‐stage development programs spanning rare genetic, neurologic, cardiovascular, metabolic, and infectious diseases. Despite these advances, oligonucleotide development presents unique challenges compared with small molecules and biologics, including rapid plasma distributive clearance, nuclease‐mediated degradation, limited extrahepatic distribution, and prolonged pharmacodynamic effects driven by tissue retention and intracellular mechanisms such as RNA‐induced silencing complex loading or RNase H‐mediated activity. Consequently, tissue disposition and intracellular pharmacology most often govern therapeutic response more directly than plasma exposures alone, complicating conventional approaches to dose selection, efficacy prediction, and safety assessment. Model‐informed drug development (MIDD) offers a quantitative framework to address these challenges through integration of preclinical, translational, and clinical data into empirical, mechanistic, and systems‐level models. This review summarizes current and emerging MIDD applications in oligonucleotide therapeutics, with primary emphasis on siRNAs and complementary insights from ASOs. Approaches discussed include empirical and semi‐mechanistic pharmacokinetic/pharmacodynamic (PK/PD) models, physiologically based pharmacokinetic (PBPK) frameworks describing tissue‐selective biodistribution and intracellular disposition, and quantitative systems pharmacology (QSP) models linking molecular target modulation with downstream biologic and clinical responses. Collectively, these approaches have supported cross‐species translation; human dose selection; clinical trial optimization; and mechanistic understanding of oligonucleotide absorption, distribution, metabolism, excretion, and pharmacology. Finally, we discuss future opportunities and remaining challenges for MIDD in oligonucleotide therapeutics, including enabling extrahepatic delivery, characterizing interindividual variability, and integrating systems‐level and data‐driven approaches to improve translational predictability and accelerate development of next‐generation oligonucleotide medicines.

Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies

This review first provides a concise overview of the mechanistic principles underlying oligonucleotide function and commonly employed chemical modification techniques, and highlights recent advancements in receptor-mediated delivery systems for extrahepatic targeting, and dual-targeting oligonucleotide engagement strategies.

RNA Therapeutics Beyond mRNA- siRNA, Antisense Oligonucleotide and microRNA as next generation pharmaceutical modalities- formulation, delivery and clinical progress

With highly targeted methods for controlling gene expression and treating a wide range of genetic, metabolic, viral, and cancerous disorders, RNA therapies have become a revolutionary technique in contemporary medicine. The main kinds of RNA (ribonucleic acid) treatments, such as antisense oligonucleotides (ASOs), small interfering RNA (siRNA), and microRNA (miRNA), are thoroughly reviewed in this study along with their methods of action, therapeutic uses, and most recent clinical developments. With a focus on viral and non-viral delivery methods such as lipid nanoparticles, liposomes, polymeric carriers, and viral vectors, this review also covers the formulation and delivery strategies used to enhance the stability, cellular uptake, and target specificity of these compounds. A comprehensive analysis is conducted of current issues, such as nuclease degradation, immune recognition, off-target effects, restricted extrahepatic distribution, and formulation-related hurdles. Furthermore, the expanding clinical value of these technologies is demonstrated by current clinical trials and recent advancements in FDA-approved RNA-based therapies. Promising approaches to circumvent current constraints are also highlighted, such as chemical changes, ligand-targeted delivery systems, formulations based on nanotechnology, and artificial intelligence-assisted therapeutic design. All things considered, RNA therapeutics are a quickly developing discipline with enormous promise to improve precision medicine and offer efficient treatment choices for illnesses that are still challenging to treat with traditional medicines.

Rational Design and Selection of Angiotensinogen-Targeting siRNA Candidates for the Treatment of Hypertension

Hypertension is a major risk factor for cardiovascular disease and often requires lifelong treatment, making poor medication adherence a major clinical challenge. RNA interference offers a potential long-acting alternative by suppressing the production of disease-related proteins at the mRNA level. Angiotensinogen (AGT), the liver-derived precursor of the renin-angiotensin-aldosterone system, is a promising target because reducing AGT expression may decrease downstream angiotensin II production and lower blood pressure. In this paper, candidate small interfering RNA sequences targeting human AGT were generated and evaluated using a rational computational screening framework. All possible 21-nucleotide target windows were assessed using sequence-based criteria, including GC content, homopolymer formation, and predicted guide-strand self-pairing. Of 1,411 possible target windows, 178 passed the initial filters, and the highest-ranked candidates had GC contents between 38.1% and 47.6% with no runs of four identical nucleotides. Candidates were prioritized through composite scoring that favored moderate GC content, homopolymer avoidance, and limited predicted intramolecular structure. These results provide a focused set of AGT-targeting siRNA candidates for future evaluation of off-target effects, delivery efficiency, target accessibility, and gene-silencing activity. Because the findings are in silico, experimental validation is required before therapeutic conclusions can be drawn. This framework represents an initial computational step toward developing long-acting RNA interference therapies for hypertension.

Progress in siRNA nucleic acid therapeutics and challenges in their application to cancer treatment.

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

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.