Oligonucleotide Drug Delivery: New Concepts and Therapeutic Opportunities

Oligonucleotide therapeutics, including antisense oligonucleotides, siRNAs, aptamers, splice-switching oligonucleotides, and related nucleic acid modalities, have transformed the landscape of drug discovery by enabling precise modulation of biological targets that are difficult or impossible to address with conventional small molecules. Yet, despite major advances, safe, efficient, and tissue-selective delivery remains the central barrier to broader clinical translation, especially beyond the liver and other locally accessible compartments. Oligonucleotides have also been utilized in the design and engineering of delivery systems, providing specific targeting ligands. More recently, nucleic acids have also been used to significantly improve therapeutic loading and control therapeutic release, with clinical translation on the horizon.This Research Topic will highlight the convergence of RNA biology, structural RNA biochemistry, nucleic acid engineering, biomaterials, nanotechnology, and experimental pharmacology in addressing delivery challenges and expanding therapeutic opportunities. It will provide a forum for studies that advance understanding of how oligonucleotides can be used in drug delivery systems and how oligonucleotide therapeutics can be designed, formulated, targeted, and released in ways that improve pharmacological performance and translational potential.We also welcome contributions that bring a structure-guided perspective to oligonucleotide design. Just as modified amino acids can be incorporated into peptides to induce specific conformations and optimize inhibitory activity, chemically modified nucleotides may be used to control RNA structure, stability, and target engagement. In this context, we are particularly interested in studies exploring the rational design of novel, site-specific RNA-based inhibitors, including approaches that use nucleotide modification to stabilize functional conformations, enhance molecular recognition, or improve inhibition of challenging biological targets such as proteases and other disease-relevant proteins.We invite contributions that move beyond descriptive formulation studies to provide mechanistic insight into oligonucleotide intercalation, drug release, and/or the interactions between oligonucleotide drugs, biological targets, tissues, and delivery systems. Of particular interest are studies that clarify structure-activity relationships, conformational design, intracellular trafficking, endosomal escape, biodistribution, pharmacokinetics, controlled release behavior, and translational performance of oligonucleotides, oligonucleotide therapeutics, and their carriers. The goal is to capture both foundational and application-driven advances that support the next generation of oligonucleotide pharmacology, drug discovery, and oligonucleotide-designed carriers.We welcome submissions on, but are not limited to, the following themes:o therapeutic oligonucleotide design and chemical modificationo structure-guided RNA design and conformational engineeringo novel, site-specific RNA-based inhibitors and functional oligonucleotide scaffoldso targeted and tissue-selective delivery strategieso aptamer-based and ligand-directed delivery systemso biomaterials, nanoparticles, and biohybrid delivery platformso controlled, sustained, and stimuli-responsive releaseo cellular uptake, intracellular trafficking, and endosomal escapeo pharmacokinetics, biodistribution, safety, and toxicologyo preclinical and translational studies supporting oligonucleotide drug discovery Topic editors: Mark Byrne, Jacek Wower Source: https://www.frontiersin.org/research-topics/80105/oligonucleotide-drug-delivery-new-concepts-and-therapeutic-opportunities