Prof. Chen Peng from the College of Chemistry and Molecular Engineering and Prof. Yi Chengqi from the School of Life Sciences, both at Peking University, have spearheaded a state-of-the-art translational research program. Together, they have rolled out a pioneering RNA codon expansion platform. This groundbreaking technology makes it possible to engineer proteins with exacting specifications in mammalian cells, a major milestone for synthetic biology and biomanufacturing. The findings were published in the esteemed journal Nature on June 25, 2025, under the title “RNA codon expansion via programmable pseudouridine editing and decoding” (DOI: 10.1038/s41586-025-09165-x).
Our RNA codon expansion platform solves a long-standing, unmet need in basic and applied molecular biology. Translation termination interference due to stop codon reprogramming. We’re here to say thanks to researchers this hurdle has been cleared! Their approach uses a new method to insert multiple noncanonical amino acids (ncAAs) with exquisite precision into proteins without changing the natural genetic code.
Groundbreaking Research and Publication
With this groundbreaking research, Jiangle Liu and his team have opened a new chapter in the field of protein engineering. By leveraging post-transcriptionally modified RNA codons in select transcripts, the group was able to efficiently encode ncAAs in mammalian systems. This approach combines two core processes: encoding and decoding, which work together to facilitate the incorporation of these unique amino acids.
Our publication in Nature focuses on the exciting implications of this work for future scientific breakthroughs. The authors first demonstrated the site-specific incorporation of ncAAs into proteins by innovative methods. This major breakthrough has created exciting new opportunities for drug development, synthetic biology, and advanced therapeutics. This unprecedented codon expansion strategy holds promise for greater precision control of protein structure and function.
Mechanism of Action
This allows for a high degree of efficiency and accuracy, producing full-length proteins with the desired modifications to complete E. coli protein synthesis. The most curious and powerful part of the system is its decoder tRNA. It indicates a codon’s strong bias in favor of its matching ΨCodon, strongly preferring it to native codons. This specificity has a critical function in maintaining orthogonality across the mammalian translatome. It gives researchers unprecedented power to control protein synthesis while preventing off-target interactions.
Three unique ΨCodon–decoder tRNA pairs were shown to be mutually orthogonal, adding additional robustness to the platform. This reciprocal orthogonality allows the concurrent addition of various ncAAs bearing distinct side chains into mammalian proteins. In a second respect, it paves the way for unprecedented customization in protein engineering.
Implications for Future Research
The human impact of this research reaches far beyond the ivory tower. Engineering proteins with non-canonical amino acids (ncAAs) has the potential to transform academic research, biopharmaceutical development, and biomanufacturing. From pharmaceuticals to materials science to agricultural biotechnology. Researchers are just beginning to scratch the surface of what this new RNA codon expansion platform can do. Their research should result in new targeted therapies and smart biomaterials.
The level of accuracy provided by this new technology will help us make meaningful advances in our understanding of complex biological systems. This technology gives researchers the ability to insert or delete specific amino acids in proteins. By doing so, it greatly accelerates investigations for disease mechanisms and therapeutic interventions.