AI-Designed Protein Boosts RNA Delivery Efficiency, Cuts Required Dose

German researchers have developed a new carrier that uses protein structures designed with generative artificial intelligence (AI) to deliver ribonucleic acid (RNA) into cells more efficiently.

According to Aju Life Science on the 3rd (local time), a research team from Helmholtz Munich and the Technical University of Munich (TUM) combined natural protein components with synthetic protein structures designed using generative AI to create a new RNA carrier called a synthetic transport vehicle (STV).

RNA-based therapies use RNA as a blueprint to prompt cells to produce specific proteins. For this process to work, RNA must reach the inside of cells intact. Viral vectors and lipid nanoparticles (LNPs) have traditionally been used, but both approaches have limitations, so the research team designed a more efficient delivery mechanism.

The team tested more than 100 variants and found that proteins with geometric structures not found in nature performed particularly well. It selected STV-C8 as the most efficient candidate.

“We did not try to reproduce nature; we designed a new structure for the specific task of efficiently delivering RNA,” said Dr. Christoph Gruber. “A key finding is that structures that differ substantially from natural viral capsids work particularly well,” said Dr. Maren Kirsten Schumacher. “This shows the potential to systematically expand the protein design space using AI.”

In cell culture experiments, STV-C8 delivered RNA much more efficiently than the viral-like particles and lipid nanoparticles used for comparison. Its transfection rate was substantially higher than that of lipid nanoparticles, and much less RNA was needed to produce a similar amount of protein.

The carrier can transport a variety of RNA cargoes and can be modified to target specific cells. “This modular structure allows the carrier to be adapted for different applications and target cells,” said Dr. Florian Giesert.

The team also conducted animal experiments to determine whether the carrier works in vivo. After intravenous injection in mice, STV-C8 induced RNA expression primarily in the lungs, and no immune or toxic side effects were observed. The team also loaded components of the CRISPR/Cas9 system into the carrier and injected it into pig muscle, successfully removing a disease-associated region of the dystrophin gene linked to Duchenne muscular dystrophy.

STV-C8 is still at the experimental stage. Further research is needed on targeting specific cell types and its distribution in the body before it can be used medically. “We have created a platform that can be developed for a range of therapeutic applications,” said Professor Wolfgang Wurst. The team plans to transfer the technology to a spin-off company.

The findings were published in the international journal Nature.