The COVID-19 pandemic has brought RNA therapeutics into the spotlight. As both carriers of genetic information and executors of biological functions, different RNAs play critical roles in regulating life processes. RNA therapeutics have emerged as promising interventions for genetic, infectious, and malignant diseases, with mRNA vaccines now leading the field.

RNA therapeutics are broadly defined as targeted treatments based on specific RNA sequences. Current research focuses on three main directions: Antisense Oligonucleotides (ASO) , RNA interference (RNAi) , and Messenger RNA (mRNA) therapeutics.

ASO Therapy – the earliest developed – uses single-stranded oligonucleotides (15–25 nucleotides) that bind to complementary target mRNA via base-pairing, inhibiting gene expression through RNase H1 activity. The first ASO drug, Fomivirsen, was approved by the FDA in 1998 for CMV retinitis. Today, multiple ASO drugs are approved, making ASO the most widely approved RNA drug class. In 2019, NMPA approved Nusinersen for spinal muscular atrophy—the first RNA drug approved in China.

RNAi Therapy harnesses a natural defense mechanism against foreign genetic material, primarily through small interfering RNA (siRNA) and microRNA (miRNA) . siRNA forms the RNA-induced silencing complex (RISC), leading to target mRNA degradation. In 2006, Andrew Fire and Craig Mello received the Nobel Prize in Physiology or Medicine for their discovery of RNA interference. The first siRNA drug, Patisiran, was approved by the FDA in 2018 for hereditary transthyretin-mediated amyloidosis with polyneuropathy.

mRNA Therapy—the newest of the three—encodes proteins by delivering exogenous mRNA into target cells, which then synthesize the desired protein. In 1990, Jon Wolff first reported intramuscular injection of mRNA into mouse skeletal muscle achieving protein expression. Since then, mRNA therapeutics have been extensively studied for infectious disease vaccines and cancer immunotherapy.

From the 1970s concept of ASO to the mRNA COVID-19 vaccines of today, over 50 years of relentless research—marked by both setbacks and breakthroughs—has transformed RNA therapeutics from a niche genetic treatment into one of the most promising therapeutic modalities.