Purpose <p>Liver cancer is the 6^th most common cancer and the 4th leading cause of cancer death worldwide. The high mortality rate is primarily due to delayed diagnosis of the liver cancer. Chemoembolization and radioembolization are known effective treatments for intermediate to advance staged liver cancer. However, the treatments are currently performed separately. This study aimed to develop a theranostic microspheres loaded with both radioactive Samarium-153 oxide ([¹⁵³Sm]Sm₂O₃) and chemotherapy drug, Doxorubicin (Dox) for chemo-radioembolization.</p> Methods <p>The sulphonated polystyrene (SPS) microspheres loaded with [¹⁵²Sm]Sm₂O₃ was synthesized using solvent evaporation synthesis. The Dox was then loaded on to the microspheres through electrostatic interactions. The synthesized [¹⁵²Sm]Sm₂O₃- and Dox-loaded polystyrene ([¹⁵²Sm]Sm₂O₃-Dox-SPS) microspheres were then neutron activated in a nuclear research reactor (TRIGA MARK II, General Atomics). Physicochemical properties, Dox loading capacity, radionuclide impurities, radionuclide retention efficiency of the microspheres were evaluated.</p> Results <p>The microspheres had an average diameter of 31.95 ± 0.26&#xa0;μm and all microspheres were within 15 to 60&#xa0;μm. The microspheres achieved a nominal specific radioactivity of 2.82 ± 0.6 GBq/g. No radionuclide impurities were observed in the microspheres after neutron activation. The encapsulation efficiency and loading capacity of Dox on the [¹⁵²Sm]Sm₂O₃-Dox-SPS microspheres was determined as 55.6 ± 1.1% and 0.55 ± 0.01%, respectively. The retention of ¹⁵³Sm on the microspheres was more than 99% in phosphate buffered saline solution up to 300&#xa0;h.</p> Conclusion <p>In conclusion, the microsphere loaded with both radioactive [¹⁵³Sm]Sm₂O₃ and Dox was successfully developed. The formulation met all the desirable physicochemical properties for intraarterial chemo-radioembolization of liver tumours.</p>