Intrinsically radiolabeled inorganic nanoparticles represent a new paradigm in personalized treatment of cancer. To minimize their potential side effects for future clinical translation, it is desirable to explore biocompatible materials for synthesis of the cancer-targeting nanoparticles. In this study, we report a unique human serum albumin (HSA)-mediated biomineralization process for synthesis of intrinsically radiolabeled [Lu-177]Lu2O3 nanoparticles entrapped in a protein scaffold ([Lu-177]Lu2O3-HSA nanocomposite). Various instrumental techniques such as X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), dynamic light scattering (DLS), transmission electron microscopy (TEM), etc. were utilized for characterization of as-synthesized nonradioactive nanoparticles. The intrinsically Lu-177-labeled nanoparticles demonstrated excellent in vitro and in vivo stability in preclinical settings. Cell binding and toxicity studies demonstrated the binding affinity and specificity of the intrinsically radiolabeled nanoparticles toward melanoma (B16F10) cells for use as a radiotherapeutic agent. Biodistribution studies demonstrated rapid and enhanced accumulation of the radiolabeled nanoparticles in the tumor (11.7 +/- 2.1%ID/g at 4 h post-injection) with significant retention up to 7 days. The therapeutic efficacy of the [Lu-177]Lu2O3-HSA nanocomposite was demonstrated by tumor regression studies performed over a period of 21 days. The encouraging results obtained in this study demonstrate the potential of the [Lu-177]Lu2O3-HSA nanocomposite for clinical translation. This strategy will also facilitate the synthesis of other radiolabeled biocompatible nanoparticles for use in cancer theranostics.