Overcoming PEG Antigenicity: Statistical PEG Isomers Reduce Antibody Binding

Poly(ethylene glycol) (PEG) is widely used in bioconjugation and nanomedicine due to its advantageous properties including solubility, biocompatibility, and pharmacokinetic benefits. However, PEG exposure can elicit anti‐PEG antibodies (APAs), resulting in accelerated blood clearance and immune responses. To address this, “randomized PEG” (rPEG) is synthesized by incorporating the comonomer glycidyl methyl ether into PEG via anionic ring‐opening polymerization. This structural isomer introduces “synthetic point mutations”, impeding APA recognition. The interaction between rPEGs and APAs is systematically investigated in buffer solution using microscale thermophoresis and fluorescence correlation spectroscopy. Increasing comonomer content drastically reduced antibody binding, with rPEGs containing 52 mol% comonomer effectively preventing APA interaction. Monte Carlo simulations confirmed a reduction in consecutive ethylene glycol sequences to less than 16 units crucial for APA recognition. These results establish rPEG as a promising PEG alternative, mitigating immune recognition while retaining key properties. This is of key relevance for next‐generation stealth polymers with improved biocompatibility for biomedical applications.