Polyethylene glycol (PEG) is a polymer with different molecular weights formed by the polymerization of ethylene oxide monomers. Due to its ability to significantly reduce the immunogenicity of protein drugs and extend their half-life, as well as its high safety profile, it has been approved by the U.S. Food and Drug Administration (FDA) as the gold standard for delivering protein drugs. Although numerous PEGylated protein drugs have been marketed, the focus of research on PEGylated protein drugs has primarily been on reducing immunogenicity and extending in vivo circulation half-life. However, the understanding of how PEG modification affects the structure and function of proteins is still limited, with “activity” often being the sole criterion for evaluating changes in protein structure and function. A deeper exploration of the existence and interaction between PEG chains and proteins is of great significance for understanding the properties exhibited by PEGylated proteins. This review summarizes strategies for PEG site-specific modification of proteins, the interaction states between PEG and proteins, and the effects of PEG chains on protein spatial structure, solubility, activity, and thermal stability. It also summarizes the characterization techniques for PEG–protein interactions, aiming to predict or explain the functions of PEGylated protein drugs through the analysis of PEG–protein interactions.

Polyethylene glycol (PEG)  /  Site-specific PEGylation  /  Protein conformation  /  Protein functionality  /  PEGylated proteins  /  Nanomedicine  /  Bioconjugation  /  Drug delivery