Longitudinal PET Imaging Reveals the Biological Fate, Pharmacokinetics, and Clearance of Zirconium-89-Labeled MXene Nanosheets In Vivo

Two-dimensional MXene (Ti3C2Tx) nanosheets have emerged as versatile platforms for drug delivery, photothermal and photodynamic therapy, combined chemo-photothermal treatment, and multimodal imaging including MRI and CT, as well as theranostic applications.However, their clinical translation is limited by an incomplete understanding of their long-term in vivo fate, pharmacokinetics, and biological interactions following systemic administration.Here, we developed a stable zirconium-89-labeled MXene platform via DFO-mediated chelation to enable quantitative, noninvasive, and longitudinal positron emission tomography (PET) imaging over 21 days.Comprehensive physicochemical characterization confirmed successful synthesis, surface functionalization, and radiolabeling of MXene nanosheets, yielding a radiochemical purity of 99.39 ± 0.66% and serum stability exceeding 97.3±1.9% over 7 days.PET/CT imaging and biodistribution studies revealed an initial pulmonary accumulation phase (30.43 ± 5.39 %ID/g), followed by progressive sequestration within the reticuloendothelial system, predominantly in the liver (maximum 30.16 ± 5.42 %ID/g on day 7) and spleen (9.31±3.17%ID/g on day 7).Quantitative biodistribution analysis further demonstrated prolonged organ retention with gradual elimination through both renal and hepatobiliary pathways, as confirmed by excretion studies.Minimal skeletal uptake (<1.04±0.14%ID/g throughout the study) indicated excellent in vivo radiolabel stability.Histopathological examination of major organs, together with in vitro cytotoxicity assays, revealed no significant adverse effects despite prolonged tissue retention.Collectively, these findings provide insight into the nano-bio interactions governing MXene biodistribution, organ accumulation, and clearance.More broadly, this study establishes a PET-based framework for evaluating the biological fate and safety of emerging two-dimensional nanomaterials and supports the rational development of MXene-based nanotheranostic platforms for biomedical applications.