With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of gamma-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy (TRT). GT3 was loaded into liposomes using passive loading. [Cu]-GT3-Nano and H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. Radioprotection efficacy of GT3-Nano was assessed after acute Cs whole-body irradiation at sublethal (4 Gy), lethal (9 Gy), or single high-dose [Sm]-EDTMP administration. Flow cytometry was used to analyze hematopoietic cell population dynamics and fluorescence microscopy was used to assess the cellular site of GT3-Nano localization in the spleen and bone marrow. Bone marrow uptake and retention of [Cu]-GT3-Nano was 6.98 ± 2.34 %ID/g, while [H]-GT3-Nano uptake and retention was 7.44 ± 2.52 %ID/g at 24 h, respectively. GT3-Nano administered 24 hours before or after 4 Gy TBI promoted rapid and complete hematopoietic recovery while recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9 Gy TBI. Flow cytometry of bone marrow indicated progenitor bone marrow cells MPP2 and CMP cells were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. GT3-Nano is highly effective in mitigating marrow suppressive effects of sub-lethal and lethal TBI in mice. GT3-Nano can aid in rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent [Sm]-EDTMP.Copyright © 2020 by the Society of Nuclear Medicine and Molecular Imaging, Inc.