Navigating the next frontier in biomedicine: breakthroughs and insights in nucleic acid therapeutics

Abstract

Nucleic acid therapeutics are rapidly emerging as a transformative drug paradigm, offering precise and programmable regulation of gene expression across a broad spectrum of diseases. This review summarizes recent advances in key platforms—including antisense oligonucleotides, siRNA, miRNA, mRNA, and aptamers—emphasizing their unique mechanisms of action and therapeutic potential. We systematically outline critical contributions of chemical modification and delivery engineering, including backbone and sugar modifications, site-specific design, N-acetylgalactosamine (GalNAc) conjugation, and lipid nanoparticles, which collectively enhance stability, target specificity, and clinical applicability. Finally, we discuss persistent challenges such as immune activation, large-scale manufacturing, and long-term safety, and provide perspectives on future directions involving CRISPR-based gene editing, synthetic biology, nanotechnology, smart delivery systems, and combination therapies, aiming to offer strategic insights for the development and clinical translation of nucleic acid drugs.