Lipid-based nanoparticles are organic nanostructures constituted of phospholipids and cholesterol, displaying high in vivo biocompatibility. They have been demonstrated as effective nanocarriers for drug delivery and targeting. Mapping liposome distribution is crucial as it enables a precise understanding of delivery kinetics, tissue targeting efficiency, and potential off-target effects. Recently, ruthenium-encapsulated liposomes have shown potential for targeted drug delivery, photodynamic therapy, and optical fluorescence imaging. In the present work, we design Ru(bpy)3-encapsulated liposomes (Ru-Lipo) empowering optical and X-ray fluorescence (XRF) properties for dual mode imaging and demonstrate the passivation role of liposomes over the free Ru(bpy)3 compound. We employ whole-body XRF imaging to map the in vivo biodistribution of Ru-Lipo in mice, enabling tumor detection and longitudinal studies with elemental specificity and resolution down to the sub-millimeter scale. Quantitative XRF computed tomography on extracted organs permits targeting efficiency evaluations. These findings highlight the promising role of XRF imaging in pharmacokinetic studies and theranostic applications for the rapid optimization of drug delivery and assessment of targeting efficiency.