Small nucleic acid therapeutics: delivery breakthroughs, clinical translation, and future paradigms in precision...

Small nucleic acid therapeutics (SNATs) are reshaping precision medicine by selectively targeting disease-associated nucleic acids, offering curative potential for genetically defined and previously intractable disorders. Unlike conventional drugs, SNATs-including ASOs, siRNAs, and aptamers-directly modulate oncogenes, splice variants, and non-coding RNAs through programmable Watson-Crick interactions. Despite this promise, clinical application has been constrained by nuclease degradation, short half-life, immunogenicity, and inefficient delivery. Recent advances in chemical engineering, such as phosphorothioate and locked nucleic acid modifications, together with tissue-specific delivery systems such as N-acetylgalactosamine conjugates and LNP, are overcoming these barriers, broadening therapeutic use across hepatic, neurological, and oncological indications. This review offers a systematic overview of the molecular mechanisms and classifications of SNATs, critically analyzes developmental barriers, and underscores innovative approaches to delivery. Furthermore, it summarizes the growing landscape of SNATs approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as late-stage clinical candidates, emphasizing emerging preclinical technologies. The study presents a multidimensional perspective on the translational trajectory of SNATs by integrating recent advances in structural optimization and targeted delivery, providing strategic insights to accelerate their development and application across various disease settings.