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Grafting-from ROMP-derived polynorbornene-basedUOconjugates retain bioactivity, improves stability, and evades anti-PEG recognition and could be a potential PEG alternative. 

PEGylation is the gold standard in protein‐polymer conjugation, improving circulation half‐life of biologics while mitigating the immune response to a foreign substance. However, preexisting anti‐PEG antibodies in healthy humans are becoming increasingly prevalent and elicitation of anti‐PEG antibodies when patients are administered with PEGylated therapeutics challenges their safety profile. In the current study, two distinct amine‐reactive poly(oxanorbornene) (PONB) imide‐based water‐soluble block co‐polymers are synthesized using ring‐opening metathesis polymerization (ROMP). The synthesized block‐copolymers include PEG‐based PONB‐PEG and sulfobetaine‐based PONB‐Zwit. The polymers are then covalently conjugated to amine residues of lysozyme (Lyz) and urate oxidase (UO) using a grafting‐to bioconjugation technique. Both Lyz‐PONB and UO‐PONB conjugates retained significant bioactivities after bioconjugation. Immune recognition studies of UO‐PONB conjugates indicated a comparable lowering of protein immunogenicity when compared to PEGylated UO. PEG‐specific immune recognition is negligible for UO‐PONB‐Zwit conjugates, as expected. These polymers provide a new alternative for PEG‐based systems that retain high levels of activity for the biologic while showing improved immune recognition profiles.