<p>The presence of antibodies against poly(ethylene glycol)s (anti-PEG Abs) has gained increasing attention with the expanded use of mRNA-lipid nanoparticles (LNPs). Anti-PEG Abs have been detected not only in patients who have received PEGylated therapeutics but also in healthy individuals. Concerns regarding the reduction in therapeutic efficacy of PEGylated therapeutics, as well as complement-related adverse effects caused by PEGylated therapeutic–anti-PEG Ab complexes, have been raised. PEG itself, however, has been classified as a hapten and is not inherently immunogenic. This suggests that anti-PEG Abs recognize PEG; however, anti-PEG Abs do not strongly bind to PEG. The methoxy group at the terminal end of PEG plays a critical role in its recognition. In the current study, we aimed to reduce the antigenicity of PEG by synthesizing different terminal structures of PEG. Evaluating the binding behaviors of terminal-methoxy- or main-chain-specific anti-PEG Abs revealed that increasing the hydrophobicity of the PEG terminus improves anti-PEG Ab recognition. Conversely, introducing hydrophilic groups at the PEG terminus worsens anti-PEG IgG recognition. These findings suggest that rational design of PEG terminal structures can potentially evade recognition by anti-PEG Abs, thereby improving the safety and efficacy of PEGylated therapeutics.</p>