AI-Designed Protein Nanocages Replicate Viral Self-Assembly, Opening New Frontiers in Drug Delivery
核心洞察
An international team led by POSTECH (搜索)'s Prof. Sangmin Lee and Nobel laureate Prof. David Baker used AI to design artificial proteins that self-assemble into virus-like nanocages ranging from 70 to 220 nm.
The breakthrough, published in Nature, successfully implements the natural principle of quasisymmetry, enabling a single protein to form both pentagonal and hexagonal arrangements.
The AI-designed nanocages represent a promising next-generation platform for targeted drug delivery, genetic material transport, and vaccine antigen presentation.
An international research team led by a Korean scientist has achieved a landmark breakthrough in protein engineering, successfully designing large-scale artificial protein structures that faithfully replicate the self-assembly principles found in naturally occurring viruses using artificial intelligence. The work, published in Nature on May 21, was led by Prof. Sangmin Lee of the Department of Chemical Engineering at Pohang University of Science and Technology (POSTECH (搜索)) in collaboration with Prof. David Baker of the University of Washington, recipient of the 2024 Nobel Prize in Chemistry.
The research was supported by programs of the Ministry of Science and ICT (搜索) (MSIT) of South Korea.
Protein Nanocages (搜索) as a Next-Generation Drug Delivery Platform
Protein nanocages (搜索) — hollow, nanometer-scale structures formed through the spontaneous binding of multiple proteins — have emerged as one of the most promising materials in the biomedical field for next-generation drug delivery. These structures can stably carry drugs, genetic materials, and enzymes within their interior space, while antigens can be attached to their outer shell.
However, existing design technologies have largely depended on computationally derived "perfect symmetric structures," which severely limits the size and complexity of structures achievable from a single protein building block.
Replicating Nature's Blueprint Through Quasisymmetry
Viruses found in nature use a single type of protein repeated hundreds to thousands of times, subtly adjusting the position and local environment of each protein to construct massive shells. This principle, known as quasisymmetry, has now been successfully implemented in the design of artificial proteins for the first time.
The research team recognized that the key to expanding viral shell size lies in the angles and curvature between protein building blocks. When proteins are arranged too flatly, the shell fails to close; when the curvature is too great, the structure becomes too small. By precisely engineering this balance, the team induced a single protein to simultaneously occupy both pentagonal and hexagonal environments depending on its position within the assembly.
To achieve this, a trimeric unit — a cluster of three proteins — was used as the basic building block, and RFdiffusion, an AI-based protein structure generation tool, was employed to design novel connecting structures. The approach, analogous to stacking interlocking building blocks at different angles, enabled the proteins to fit together at varying orientations, producing a massive dome-shaped shell rather than a flat sheet.
Experimental Validation via Cryo-Electron Microscopy
The team produced the designed artificial proteins using E. coli and observed their morphology using state-of-the-art cryo-electron microscopy. The results confirmed that the proteins spontaneously assembled into spherical shells ranging in size from a minimum of 70 nm to a maximum of 220 nm. The smallest structure adopted the form of an elaborate "nano-soccer ball," while the largest was more than three times that size.
Significance and Future Applications
This study has attracted significant attention from the scientific community because it did not repurpose existing viral proteins, but instead used a single, entirely AI-designed artificial protein to freely construct large virus-like structures. If commercialized, this technology is expected to enable transformative applications across the biomedical field, including targeted drug and genetic material delivery systems and vaccine antigen presentation platforms. Follow-up research is also planned to achieve more uniform size control using internal scaffold proteins or nucleic acids as templates.
In a remarkable and rare achievement, a related study on artificial protein structures, led by Prof. Baker with Prof. Sangmin Lee as a co-author, was also published in Nature on the same date. This makes Prof. Lee the corresponding author on one paper and co-author on another published simultaneously in the world's foremost scientific journal.
Researcher Perspectives
"Viruses are the finest example in nature showing that perfect symmetry is not the only path to sophisticated molecular architecture," said Prof. Sangmin Lee of POSTECH (搜索). He explained that just as subtle changes in the angle between molecular tiles can transform a flat plane into a massive dome, this study demonstrates that precise control of local protein block geometry enables fine-tuned command over the size and shape of the final assembly.
Sung-Soo Kim, Director General for R&D Policy at MSIT, described the achievement as "a remarkable demonstration of world-class fundamental research capability by a leading Korean scientist, realized through collaboration with a Nobel laureate," adding that "MSIT will continue to provide unwavering support to advance the research capacity of Korean scientists and generate globally pioneering results."