Chemistry trick may herald transformational next-generation RNAi therapeutics

Small pieces of synthetic RNA trigger a RNA interference (RNAi) response that holds great therapeutic potential to treat a number of diseases, especially cancer and pandemic viruses.

The problem is delivery—it is extremely difficult to get RNAi drugs inside the cells in which they are needed. To overcome this hurdle, researchers at University of California, San Diego School of Medicine have developed a way to chemically disguise RNAi drugs so that they are able to enter cells. Once inside, cellular machinery converts these disguised drug precursors—called siRNNs—into active RNAi drugs.

"Many current approaches use nanoparticles to deliver RNAi drugs into cells," said Steven F. Dowdy, PhD, professor in the Department of Cellular and Molecular Medicine and the study's principal investigator. "While nanotechnology protects the RNAi drug, from a molecular perspective nanoparticles are huge, some 5,000 times larger than the RNAi drug itself. Think of delivering a package into your house by having an 18-wheeler truck drive it through your living room wall—that's nanoparticles carrying standard RNAi drugs.

Unfortunately, due to their size and negatively charged chemical groups (phosphates) on their backbone, RNAi drugs are repelled by the cellular membrane and cannot be delivered into cells without a special delivery agent.

It took Dowdy and his team, including Bryan Meade, PhD, Khirud Gogoi, PhD, and Alexander S. Hamil, eight years to find a way to mask RNAi's negative phosphates in such a way that gets them into cells, but is still capable of inducing an RNAi response once inside. In the end, the team added a chemical tag called a phosphotriester group. The phosphotriester neutralizes and protects the RNA backbone—converting the ribonucleic acid (RNA) to ribonucleic neutral (RNN).