No single clinical imaging modality has the ability to provide both high resolution and high sensitivity at the anatomical, functional and molecular level. Synergistically integrated detection techniques overcome these barriers by combining the advantages of different imaging modalities while reducing their disadvantages. We report the development of protein nanospheres optimized for enhancing MRI, CT and US contrast while also providing high sensitivity optical detection. Transferrin protein nanospheres (TfpNS), silicon coated, doped rare earth oxide and rhodamine B isothiocyanate nanoparticles, Si⊂Gd2O3:Eu,RBITC, (NP) and transferrin protein nanospheres encapsulating Si⊂Gd2O3:Eu,RBITC nanoparticles (TfpNS-NP) were prepared in tissue-mimicking phantoms and imaged utilizing multiple cross-sectional imaging modalities. Preliminary results indicate a 1:1 NP to TfpNS ratio in TfpNS-NP and improved sensitivity of detection for MRI, CT, US and fluorescence imaging relative to its component parts and/or many commercially available contrast agents.© (2011) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.