In Vivo Bioorthogonal Radiolabeling of Nanoparticles to Minimize Liver Radiation

Radiolabeled nanoparticles hold great promise in precision medicine due to its versatile applications in disease imaging and therapy. However, its clinical translation is often hindered by excessive accumulation in reticuloendothelial system organs, particularly the liver, which can lead to radiation-induced 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-cyclooctene (TCO)-functionalized iron oxide nanoparticles (Fe₃O₄@TCO) and a radiolabeled tetrazine probe (¹⁷⁷Lu-DOTA-Tz) is constructed to validate this concept. Owing to the hydrophilic nature, ¹⁷⁷Lu-DOTA-Tz cannot penetrate cell membranes, resulting in spatially restricted bioorthogonal labeling in the extracellular space. At tumor sites, Fe₃O₄@TCO nanoparticles accumulate via the enhanced permeability and retention effect and remain accessible for efficient binding with ¹⁷⁷Lu-DOTA-Tz. 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-to-liver radiation ratio. This study provides a biologically informed strategy for designing radiolabeled nanoplatforms with enhanced safety profiles for theranostic applications.