RNA Therapeutics in Clinical Translation: Oligonucleotides and RNA-Targeted Small Molecules From Discovery to Approved Drugs

The past decade has transformed what a therapeutic molecule can be. mRNA, small interfering RNA (siRNA), and antisense oligonucleotide (ASO) drugs have moved from molecular biology tools to approved medicines, with more than a dozen RNA-based drugs across these classes reaching regulatory approval since 2018 and a growing number of candidates in mid- and late-stage clinical trials. These modalities share a defining pharmacological challenge: unlike small molecules, their behavior in the body is governed by a complex interplay of formulation design, intracellular trafficking, innate immune sensing, and tissue-targeting mechanisms that traditional drug development frameworks were not built to handle.Despite this rapid progress, the translational literature remains fragmented. Formulation scientists, pharmacokineticists, immunologists, clinical pharmacologists, and RNA chemical biologists rarely publish within a shared framework, leaving the bench-to-bedside logic of RNA drug development underrepresented. This Research Topic addresses that gap directly. It draws on expertise in pharmaceutical formulation, nanocarrier-based delivery systems, preclinical pharmacokinetics, and RNA-targeted drug discovery. It brings together research that treats mRNA, siRNA, ASO therapeutics, and RNA-targeted small molecules as drugs first: how they are formulated for stability and delivery, how they distribute across tissues and act intracellularly, how safety and immunogenicity are characterized and managed, how RNA-targeted small molecules are discovered and optimized, and what lessons from approved RNA therapeutics, including risdiplam, can accelerate the next generation of medicines. The goal is to build an integrated, translational reference collection for researchers, clinicians, and industry scientists working at the intersection of molecular pharmacology and drug development.This Research Topic welcomes contributions focused on: lipid nanoparticle (LNP) formulation and optimization studies that connect formulation design to biodistribution, pharmacodynamics, or safety outcomes; pharmacokinetics, tissue distribution, and intracellular trafficking of oligonucleotides; innate immune activation, immunogenicity biomarkers, and mitigation strategies; organ-selective delivery beyond the liver (CNS, lung, muscle, tumor); PK/PD modelling for preclinical-to-clinical translation; clinical pharmacology and regulatory bioanalysis of approved RNA drugs; and the discovery, optimization, mechanism of action, pharmacology, and clinical translation of RNA-targeted small molecules, including compounds that modulate RNA structure, splicing, translation, and function. Disease-agnostic and indication-specific contributions are equally welcome. We invite Original Research, Reviews, Mini Reviews, Hypothesis and Theory articles, and Perspectives. Submissions focused solely on non-coding RNA biology, meta-analyses, or cohort studies without a pharmacological intervention focus fall outside this scope.This Research Topic is distinct from the currently active Frontiers in Pharmacology Research Topic “Oligonucleotide Drug Delivery: New Concepts and Therapeutic Opportunities,” which focuses specifically on oligonucleotide delivery systems and biomaterials in the Experimental Pharmacology and Drug Discovery section. This proposal extends beyond delivery to cover the full drug development arc across mRNA, siRNA, ASO, and RNA-targeted small-molecule modalities, with particular emphasis on the pharmacokinetic, immunological, and clinical translation stages that fall outside that Research Topic’s scope. Topic editors: Dr. Sachin Sanap, MAYANK HANDA, Dr. Samarth Kumar, AMIRHOSSEIN TAGHAVI Source: https://www.frontiersin.org/research-topics/84627/rna-therapeutics-in-clinical-translation-oligonucleotides-and-rna-targeted-small-molecules-from-discovery-to-approved-drugs