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However, its clinical translation is often hindered by excessive accumulation in reticuloendothelial system organs, particularly the liver, which can lead to radiation\u2010induced toxicity. Herein, an in vivo selective radiolabeling strategy is reported that exploits the distinct subcellular fates of nanoparticles in tumors versus liver. A biorthogonal nanosystem composed of trans\u2010cyclooctene (TCO)\u2010functionalized iron oxide nanoparticles (Fe\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>4<\/jats:sub>\n                    @TCO) and a radiolabeled tetrazine probe (\n                    <jats:sup>177<\/jats:sup>\n                    Lu\u2010DOTA\u2010Tz) is constructed to validate this concept. Owing to the hydrophilic nature,\n                    <jats:sup>177<\/jats:sup>\n                    Lu\u2010DOTA\u2010Tz cannot penetrate cell membranes, resulting in spatially restricted bioorthogonal labeling in the extracellular space. At tumor sites, Fe\n                    <jats:sub>3<\/jats:sub>\n                    O\n                    <jats:sub>4<\/jats:sub>\n                    @TCO nanoparticles accumulate via the enhanced permeability and retention effect and remain accessible for efficient binding with\n                    <jats:sup>177<\/jats:sup>\n                    Lu\u2010DOTA\u2010Tz. In contrast, in the liver, nanoparticles are predominantly internalized by liver cells, and its intracellular localization prevents interaction with the probe, thereby minimizing hepatic radiation retention. By harnessing these subcellular distribution differences, the approach achieves selective in vivo radiolabeling and significantly improves the tumor\u2010to\u2010liver radiation ratio. This study provides a biologically informed strategy for designing radiolabeled nanoplatforms with enhanced safety profiles for theranostic applications.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202503438","type":"journal-article","created":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T12:10:01Z","timestamp":1759579801000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Vivo Bioorthogonal Radiolabeling of Nanoparticles to Minimize Liver Radiation"],"prefix":"10.1002","volume":"15","author":[{"given":"Yun","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD\u2010X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University  Suzhou 215123 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD\u2010X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD\u2010X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD\u2010X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University  Suzhou 215123 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD\u2010X), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions Soochow University  Suzhou 215123 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