New biomedical strategies are being developed to improve the sensitivity and resolution of in vivo diagnostic imaging modalities for early and accurate diseases detection, for guided interventional treatments and for therapeutic monitoring in a number of conditions with special reference to cardiovascular disorders. Several iron oxide-based contrast agents are available to discriminate between healthy and pathological tissues; however, especially with reference to the circulatory system, their limited circulation in the bloodstream hampers their use. In fact, iron oxide nanoparticles (NPs), independently of their size, coating and shape, are rapidly removed from circulation by phagocytic cells of the liver, spleen, lungs and bone marrow. Several attempts to overcome these limits by new biomimetic constructs have only marginally solved the problem. Herein, we describe the use of red blood cells (RBCs) as carriers for contrast agents useful to overcome these limits. RBCs have unique properties that, under careful controlled conditions, permits their reversible opening without losing their natural features and functionalities. The in vivo survival of these RBC constructs was found to mimic the natural RBC survival with increase in the half-life of the NPs from less than 1 h to 4.5 days once loaded into RBC in mice. First in vitro and in vivo results obtained by using RBC loaded with superparamagnetic iron oxide particles (SPIO) or ultrasmall superparamagnetic iron oxide particles (USPIO) nanoparticles in diagnostic applications, such as magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), confirmed the advantages and extended the imaging window from few minutes to several days. These results should now be confirmed in MRI and MPI diagnostic applications in clinical settings.