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Herein, how PEGylation affects the in vivo behavior of peptide radiopharmaceuticals is investigated, focusing on the length and topological structure of the PEG molecules. A peptide ligand that targets CD133 is used and modified with different lengths of PEG (PEG\n                    <jats:sub>3<\/jats:sub>\n                    , PEG\n                    <jats:sub>10<\/jats:sub>\n                    , and PEG\n                    <jats:sub>20<\/jats:sub>\n                    ) to study the impact of PEG length. Additionally, a peptide ligand targeting PD\u2010L1 is modified with single\u2010arm PEG, 4\u2010arm PEG, and 8\u2010arm PEG to examine the effects of PEG polyvalency. Through quantitative PET\/CT imaging for long\u2010term tracking, the in vivo behavior of the synthesized peptide radioligands is compared. Interestingly, PEG\n                    <jats:sub>10<\/jats:sub>\n                    is the optimal spacer for achieving maximum tumor retention for the CD133\u2010targeting peptide. However, the PD\u2010L1 peptide derivatives modified with different armed PEG molecules showed complex results, with increased PEG arms leading to a higher tumor therapeutic index but compromising the pharmacokinetic properties. The findings highlight the dual nature of PEGylation in peptide radiopharmaceutical development, emphasizing the importance of considering PEG size, structure, and attachment point in drug design process. This study shed light on the diverse effects of PEGylation and aids in discovering PEGylated radiopharmaceuticals.\n                  <\/jats:p>","DOI":"10.1002\/smll.202410410","type":"journal-article","created":{"date-parts":[[2025,6,29]],"date-time":"2025-06-29T10:24:34Z","timestamp":1751192674000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Precise PEGylation Modulates the in Vivo Fate of Peptide Radiopharmaceuticals"],"prefix":"10.1002","volume":"21","author":[{"given":"Jieting","family":"Shen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingkai","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Advanced Nuclear Medicine Sciences Institute for Quantum Medical Science National Institutes for Quantum Science and Technology  Chiba 263\u20108555 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiding","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Advanced Nuclear Medicine Sciences Institute for Quantum Medical Science National Institutes for Quantum Science and Technology  Chiba 263\u20108555 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qichen","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia Medica Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100050 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Preclinical Study for New Drugs of Gansu Province School of Basic Medical Sciences &amp; 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