The AI-designed protein shell STV-C8 carries RNA into cells more efficiently than lipid nanoparticles
Teams at Helmholtz Munich and the Technical University of Munich combined natural protein building blocks with a scaffold designed by generative AI to build a class of RNA carrier they call the Synthetic Transfer Vehicle. More than a hundred variants were screened, and the most efficient of them, STV-C8, delivered RNA into cultured cells markedly better than the lipid nanoparticles and virus-like particles tested. The team gave it intravenously to mice and injected it into a pig's muscle with CRISPR-Cas9 components, editing the dystrophin gene.
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STV-C8 stood out among more than a hundred variants
Teams at the Institute of Stem Cell Research and the Institute of Developmental Genetics at Helmholtz Munich and the Technical University of Munich built the RNA carrier from the ground up. They combined functional protein building blocks with a structural protein designed by generative AI; that protein forms the vehicle's scaffold and can take shapes that do not occur in nature. The team tested more than a hundred variants. Structures with non-natural geometries performed particularly well, and STV-C8 was the most efficient candidate. Christoph Gruber, a co-first author, says the team set out to design new structures for one task, the efficient delivery of RNA, rather than to recreate nature. The peer-reviewed paper appeared in Nature.[1], [2]
In cell culture, STV-C8 moved ahead of lipid nanoparticles
In cell culture, STV-C8 reached a markedly higher transfection rate than the lipid nanoparticles and virus-like particles tested, and it needed markedly less RNA to yield the same amount of protein. Lipid nanoparticles, the fat-like carriers used in messenger-RNA vaccines, are hard to aim at a chosen tissue, while a protein shell can in principle be redesigned for a target. The shell can be loaded with different RNA cargoes and directed at different target cells. Florian Giesert, who leads the gene-editing group at the Institute of Stem Cell Research, treats that modularity as the way to adapt the carrier to separate applications and target cells.[1], [2]
Lungs in mice, a CRISPR-Cas9 edit in pig muscle
The team gave the carrier intravenously to mice; the delivered RNA was expressed mainly in the lungs, and the researchers found no sign of immunological or toxic side effects. They loaded STV-C8 with CRISPR-Cas9 components and injected it into a pig's muscle, where they removed a disease-relevant section of the dystrophin gene, which encodes a protein that stabilises muscle cells and is disrupted in Duchenne muscular dystrophy. STV-C8 remains an experimental system: how the vehicles can be aimed at particular cell types, and how they distribute through the body, are open questions before any medical use. Wolfgang Wurst, the last author, says the team plans to carry the platform into a spin-off company.[1], [2]
