RNA interference (RNAi) is a natural mechanism for regulating gene expression, also known as post-transcriptional gene silencing (PTGS), and is found in a variety of organisms including plants, animals, fungi, and some bacteria.

This ancient evolutionary defense mechanism against viruses has been adapted by molecular biologists for gene silencing, making it a powerful tool in genetic research.

The RNAi pathway is primarily directed by two molecules: short interfering RNA (siRNA) and microRNA (miRNA), which induce gene silencing through a four-step process.

The process begins when double-stranded RNA (dsRNA) is processed by Dicer, an endoribonuclease, into short segments of about 20 nucleotides.

These small RNA fragments then associate with Argonaute proteins to form the RNA-induced silencing complex (RISC), where one strand is selected as a guide strand.

The guide strand binds to complementary messenger RNA (mRNA), leading to either translation blocking by miRNA or mRNA cleavage by siRNA, effectively silencing the gene.

miRNA can target multiple mRNAs due to its ability to bind partially, while siRNA requires full complementarity with its target, resulting in high specificity and low off-target effects.

RNAi technology has been utilized for gene knockdown in various organisms, allowing researchers to study gene functions and their roles in diseases.

In medical research, RNAi is used to generate disease models and develop therapies for genetic disorders, such as targeting toxic mRNA transcripts in Huntington's disease.

The FDA approved the first RNAi-based therapy, Patisiran, in 2018, which targets mutant transthyretin gene transcripts to treat hereditary transthyretin amyloidosis.

The significance of RNAi has been recognized with two Nobel Prizes in Physiology or Medicine, awarded first in 2006 for the manipulation of gene expression using dsRNA, and again in 2024 for the discovery of miRNA.

Beyond medicine, RNAi applications extend to agriculture, where it helps control plant pathogens and develop environmentally-friendly pesticides by targeting genes in pest insects.