Cryo-EM analysis of designed de novo protein nanocages – Image Credit POSTECH
Professor Sangmin Lee of POSTECH’s Department of Chemical Engineering, working with 2024 Nobel Chemistry Laureate Professor David Baker of the University of Washington, has developed a novel AI-driven therapeutic platform that mimics complex viral structures. Their groundbreaking research was published in Nature.
Viruses, with their spherical protein shells designed to encapsulate genetic material for replication and host cell invasion (often leading to disease), have inspired researchers to explore artificial, virus-like proteins. These “nanocages” mimic viral behavior to deliver therapeutic genes to target cells. However, current nanocages are limited by their small size, restricting the amount of genetic material they can carry, and their simple designs, which fail to replicate the complex multifunctionality of natural viral proteins.
To address these limitations, the research team used AI-driven computational design. While most viruses display symmetrical structures, they also feature subtle asymmetries. Leveraging AI, the team recreated these nuanced characteristics and successfully designed nanocages in tetrahedral, octahedral, and icosahedral shapes for the first time.
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Electron microscopy confirmed the AI-designed nanocages achieved the intended precise, symmetrical structures. Functional experiments also demonstrated their effectiveness in delivering therapeutic payloads to target cells, paving the way for practical medical applications.
The resulting nanostructures are composed of four types of artificial proteins, forming intricate architectures with six distinct protein-protein interfaces. Among these, the icosahedral structure, measuring up to 75 nanometers in diameter, stands out for its ability to hold three times more genetic material than conventional gene delivery vectors, such as adeno-associated viruses (AAV), marking a significant advancement in gene therapy.
“Advancements in AI have opened the door to a new era where we can design and assemble artificial proteins to meet humanity’s needs,” said Professor Sangmin Lee. “We hope this research not only accelerates the development of gene therapies but also drives breakthroughs in next-generation vaccines and other biomedical innovations.”
