2026· The Innovation Drug Discovery· 2 citations· 116 references
TL;DR
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.
Abstract
Oligonucleotide therapeutics have demonstrated unique advantages, including the capacity to target traditionally undruggable disease targets and achieve prolonged pharmacological effects that can last up to months. This fast-evolving drug modality has been gaining momentum over the past two decades, evidenced by regulatory approval on multiple entities which mostly target liver. Nevertheless, further extending its application to extrahepatic targets is largely confined by corresponding delivery systems. This review first provides a concise overview of the mechanistic principles underlying oligonucleotide function and commonly employed chemical modification techniques. It then highlights recent advancements in receptor-mediated delivery systems for extrahepatic targeting, and dual-targeting oligonucleotide engagement strategies encompassing design principles and outcomes in complex disease condition. Finally, we discuss key challenges and future directions in the field. Collectively, ongoing innovations in chemical modification and delivery technologies are expected to broaden the therapeutic scope of oligonucleotide agents, paving the way for improved clinical outcomes across a wider range of diseases.
Antibody-oligonucleotide conjugates (AOCs) have emerged as a promising therapeutic platform that integrates the targeting capability of antibodies with the gene-regulatory potential of oligonucleotide payloads. By enabling cell or tissue selective delivery, AOCs may extend oligonucleotide therapeutics beyond liver predominant distribution and broaden intervention strategies for intracellular targets that have historically been difficult to drug. However, their therapeutic performance is not determined by target binding alone, but also by productive intracellular delivery, including receptor mediated uptake, endosomal trafficking, payload release, and functional access to cytoplasmic or nuclear compartments. In this review, we summarize the key design principles governing AOCs performance, including target biology, antibody formats, oligonucleotide payload classes, chemical modifications, linker design, conjugation strategies, and critical quality attributes. We further discuss the intracellular fate of AOCs and highlight endosomal escape as a major rate limiting step that often constrains biological activity despite efficient cellular uptake. In addition, we review current translational progress, with particular emphasis on neuromuscular disorders, as well as emerging applications in oncology, central nervous system diseases, and other indications. Finally, we outline major challenges and future directions that are likely to shape the next generation of AOCs therapeutics.
Yuqian Li, Xinlin Liu, Fuyuan Zhang et al.· Journal of Hematology & Onco...· 0 citations
Recent advances in nucleic acid science have significantly expanded the scope of precision medicine, enabling therapeutic strategies that extend beyond conventional small molecules and biologics. This review examines the development and current state of mRNA- and nucleic acid based delivery platforms, emphasizing their growing importance in next-generation therapeutics. We begin with a brief historical overview, describing early challenges related to molecular instability, inefficient targeting, and limited cellular uptake, and how progressive technological innovations have successfully addressed these limitations. The mechanisms underlying mRNA and nucleic acid drug delivery are then discussed, with particular focus on their ability to regulate gene expression and modulate immune responses with high specificity. Key delivery technologies are highlighted, including lipid nanoparticles, polymer- based carriers, and conjugate systems, along with recent formulation advances that have improved safety, efficacy, and translational potential. Ongoing challenges such as cargo degradation, unintended immune activation, and suboptimal delivery efficiency are critically evaluated, and practical strategies to overcome these barriers are presented. Basically, the review explores future directions in the field, underscoring the promise of nucleic acid therapeutics in personalized medicine and the importance of continued research to optimize delivery platforms. Overall, this article provides a comprehensive overview of the evolving landscape of nucleic acid-based therapeutics and aims to inform clinicians, researchers, and pharmaceutical scientists about their current applications and future potential in modern healthcare.
Satyaraj Ombase, Shanmugarathanam Alagarsamy, R. Prasad et al.· Adolescência e Saúde· 0 citations
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.
Paridhi Gupta, Mindy Magee, Vivaswath S. Ayyar· Journal of clinical pharmaco...· 0 citations
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.
D. Park, A. Bühler, Christian Schöllhorn et al.· Expert Opinion on Drug Disco...· 0 citations
mRNA therapeutics have garnered significant attention in recent years due to their remarkable success in addressing unmet medical needs across diverse fields, including infectious diseases, cancer, and hereditary disorders. Among the various modalities of mRNA therapeutics, self-amplifying mRNA (saRNA) has emerged as a particularly promising platform. Distinguished by its ability to achieve robust protein expression at lower doses, saRNA offers several advantages, including higher cumulative expression levels and significantly extended expression durations. But the questions of how and where saRNA technology will evolve in the coming years remain underexplored. In this review, we provide a comprehensive overview of saRNA therapeutics, beginning with a detailed explanation of their underlying mechanism of action. We then systematically summarize the preclinical and clinical advancements in saRNA-based therapies, highlighting their applications across a broad spectrum of diseases. We then discuss the key challenges currently faced by saRNA therapeutics and propose potential strategies to overcome these barriers. Finally, we outline future directions for the field, emphasizing the transformative potential of saRNA in clinical applications. In summary, the unique properties of saRNA have positioned it as an innovative tool for the treatment of various diseases, unlocking more possibilities for clinical applications.
Yan Zong, Chanyuan Jin, Q. Cheng· Small· 0 citations
The therapeutic potential of small interfering RNA (siRNA) has been increasingly realized, yet metabolic stabilization remains a central effort to further extend clinical applications and durability of the siRNA drugs. This Expert Insight discusses key considerations for designing metabolic stabilization for siRNA scaffolds, with a focus on understanding degradation mechanisms across biological environments. We examine how nuclease susceptibility, chemical modification patterns, and tissue‑specific factors influence siRNA stability and efficacy. Particular attention is given to maintaining compatibility with Argonaute 2 (AGO2)-mediated RNA interference, as excessive and/or inappropriate positioning of chemical modifications compromises target engagement, RNA‑AGO2 interaction, and thus silencing efficiency. Clinically used and recently advanced chemical modifications are highlighted. Collectively, these insights aim to guide the rational design of next‑generation siRNA therapeutics with improved metabolic stability and clinical performance.
Theodore‑Carrigan Broda, Ken Yamada· Nucleic Acid Insights· 0 citations