'One shot, four weeks of effect': Korean researchers develop RNA therapy for high cholesterol

South Korean researchers have developed a new RNA drug delivery technology that remains effective for four weeks after a single dose and can simultaneously target multiple disease-causing genes.

The National Research Foundation of Korea announced Friday that a research team led by Professor Lee Jong-beom of the chemical engineering department at the University of Seoul has developed a "fusogenic RNA nanomodule" capable of delivering large quantities of small interfering RNA (siRNA) directly into the cytoplasm and sustaining the suppression of multiple target genes.

siRNA has drawn attention as a next-generation therapeutic because it can selectively reduce the expression of specific disease-causing genes. It breaks down easily inside the body, however, and struggles to cross cell membranes, requiring a carrier to transport it safely.

Lipid nanoparticles (LNPs), the most widely used delivery vehicles today, can carry only a limited amount of RNA. Even after entering a cell, the RNA can become trapped in membrane-bound compartments called endosomes, preventing it from functioning properly — or it may be released all at once, shortening the therapeutic effect.

To address these shortcomings, the research team created CRAM, a porous RNA core densely packed with siRNA sequences, then coated it with a lipid layer capable of fusing directly with cell membranes to produce L-CRAM.

L-CRAM carries more RNA than conventional LNPs and delivers the RNA core directly into the cytoplasm by fusing with the cell membrane. Once inside, cleavage enzymes gradually break down the RNA core, continuously generating and releasing siRNA — effectively making it an RNA drug reservoir.

In liver cell experiments, L-CRAM targeting APOC3, a gene involved in triglyceride metabolism, suppressed expression of that gene by about 70 percent. The suppression effect lasted up to seven days.

By simply changing the RNA module's sequence, the platform can suppress PCSK9, ANGPTL3 and APOC3 — genes involved in blood cholesterol and triglyceride metabolism — individually or simultaneously. That means a single nanoparticle can target multiple disease-related genes at once.

Animal experiments confirmed the technology's potential. When L-CRAM was administered intravenously to mice, it reached the liver and suppressed APOC3 expression. Blood triglyceride and lipoprotein levels also fell, with the triglyceride-lowering effect lasting up to four weeks.

"This is a platform that can deliver large amounts of siRNA with a small number of particles and regulate multiple genes from a single particle," Lee said. "It could be used not only for complex metabolic diseases but also in developing long-lasting RNA therapies for cancer and inflammatory conditions."

The study, supported by the Ministry of Science and ICT and the National Research Foundation of Korea, was published in the international journal Advanced Functional Materials.