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Although conjugation of poly(ethylene glycol) (PEGylation) of UOx can improve the pharmacokinetics, preexisting or induced anti\u2010PEG antibodies, which lead to accelerate blood clearance (ABC) and reduced response rate, have been a major clinical hurdle. Herein, we report the facile \u201cgrafting\u2010from\u201d preparation of a nanourchin\u2010like uricase\u2010poly(\n                    <jats:sub>L<\/jats:sub>\n                    \u2010proline) conjugate, namely UOx\u2010PLP, with high grafting\u2010density, enhanced thermal, lyophilization, freeze\u2010thaw, and proteolytic stability. Through a transient preblocking strategy in the synthesis, the UOx\u2010PLP overcomes activity loss and retains ~82\u2009% enzyme activity. In Sprague\u2010Dawley rats, UOx\u2010PLP stimulates minimum complement activation and anti\u2010UOx antibodies. Unlike PEG\u2010UOx gave a significantly reduced half\u2010life after repetitive administrations, UOx\u2010PLP shows no sign of ABC effect. Moreover, the half\u2010life of UOx\u2010PLP remain almost unchanged when cross\u2010administrated to rats previously received PEG\u2010UOx and with high titers of anti\u2010UOx antibodies. Finally, UOx\u2010PLP shows minimum loss of efficacy after five straight administrations in a UOx knock\u2010out hyperuricemia mice model, whereas PEG\u2010UOx experiences sharp loss of efficacy upon the same treatment. Overall, the simple preparation and outstanding nonclinical results highlight the enormous potential of UOx\u2010PLP for future clinical translation.\n                  <\/jats:p>","DOI":"10.1002\/anie.202425559","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T17:50:06Z","timestamp":1741715406000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Nanourchin\u2010like Uricase\u2010Poly(\n                    <sub>L<\/sub>\n                    \u2010proline) Conjugate with Retained Enzymatic Activity, Mitigated Immunogenicity, and Sustained Efficacy Upon Repeated Administrations"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3196-2176","authenticated-orcid":false,"given":"Ruichi","family":"Zhao","sequence":"first","affiliation":[{"name":"Beijing National Laboratory for Molecular Sciences Center for Soft Matter Science and Engineering Key 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