In 1897, Felix Hoffmann synthesized acetylsalicylic acid—the world's first synthetic drug, aspirin. In 1975, Milstein and Kohler developed hybridoma technology, giving birth to monoclonal antibodies. In 1978, Paul Zamecnik demonstrated that synthetic antisense oligonucleotides could inhibit Rous sarcoma, launching nucleic acid drug research. Over 125, 77, and 44 years respectively, different drug classes have dominated different eras.

Nucleic acids—polymers of nucleotides including DNA and RNA—are fundamental to life. Nucleic acid drugs, composed of functional oligomeric RNA or DNA, directly act on pathogenic target genes or mRNAs to modulate disease at the genetic level.

Traditional small-molecule and antibody drugs bind to target proteins, limited by the druggability of the protein target. The human genome encodes approximately 20,000 proteins—only about 3,000 are considered druggable, and only ~700 have corresponding approved drugs. Antibodies primarily target extracellular or membrane-bound proteins. In contrast, nucleic acid drugs are gene-targeted therapeutics that regulate gene expression at the source—offering both symptomatic and root-cause treatment. They can target molecules inaccessible to traditional drugs (e.g., mRNA, miRNA), offering breakthrough potential for hard-to-treat diseases including genetic disorders, cancer, and emerging infections.

Nucleic acid drug development is also faster and simpler. Small-molecule discovery involves screening compounds against target proteins—a lengthy process. Nucleic acid drugs are designed based on base-pairing complementarity; any gene sequence could theoretically become a target, requiring only rearrangement of A, G, C, T(U) bases.

Despite early challenges—instability, immunogenicity, poor cellular uptake, and endosomal escape—key technological breakthroughs have resolved these issues. Since the first nucleic acid drug (fomivirsen sodium) in 1998, over 10 nucleic acid drugs have been approved, including two mRNA COVID-19 vaccines, with hundreds more in clinical trials.

With advantages of high specificity, high efficiency, long duration, and low toxicity, nucleic acid drugs—including ASO, siRNA, miRNA, saRNA, mRNA, RNA aptamers, ribozymes, and antibody-nucleic acid conjugates—are poised to become the third major drug class, following small molecules and antibodies. Billions of years ago, nucleic acids gave rise to life. Today, as humanity faces major diseases, nucleic acid drugs are rising to the challenge—opening new frontiers in drug discovery and enabling gene therapy and personalized medicine.