Advances in the Biomedical Applications of Genetic Code Expansion

Genetic code expansion (GCE) is an advanced and rapidly evolving technology in chemical biology and synthetic biology. By enabling the site-specific incorporation of noncanonical amino acids (ncAAs) into proteins through genetic encoding, GCE expands beyond the limitations of the 20 canonical amino acids in side-chain structure and chemical reactivity, providing a powerful synthetic biology tool for the precise engineering and functional regulation of biotherapeutics. The biomedical applications of GCE are systematically reviewed, with an emphasis on strategies that use genetically encoded ncAAs to achieve precise protein modification, function expansion, and controllable regulation. Representative applications include homogeneous drug conjugation, half-life extension, covalent protein drugs, viral vector functionalization, vaccine development, and the programmable control of engineered cells. These advances provide an important technical foundation for the development of new therapeutics, vaccine design, and cell therapy. Finally, the major challenges facing the biomedical translation of GCE are discussed, and its future potential is considered in light of advances in orthogonal translation system optimization, genome recoding, and AI-assisted design.