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Abstract: The application of superparamagnetic iron oxide nanoparticles (SPIONs) in drug delivery{,} magnetic resonance imaging{,} cell tracking{,} and hyperthermia has been long exploited regarding their inducible magnetic properties. Nevertheless{,} SPIONs remain rapidly cleared from the circulation by the reticuloendothelial system (RES) or mononuclear phagocyte system{,} with uptake dependent on several factors such as the hydrodynamic diameter{,} electrical charge and surface coating. This rapid clearance of SPION-based theranostic agents from circulation is one of the main challenges hampering the medical applications that differ from RES targeting. This work proposes a strategy to render biocompatible SPIONs through their encapsulation in the red blood cells (RBCs). In this work{,} the research has been focused on the multi-step optimization of chemical synthesis of magnetic nanoparticles (MNPs){,} precisely iron oxide nanoparticles (IONPs) and zinc manganese-ferrite nanoparticles (Zn/Mn FNPs){,} for encapsulation in human and murine RBCs. The encapsulation through the transient opening of RBC membrane pores requires extensive efforts to deliver high-quality nanoparticles in terms of chemical properties{,} morphology{,} stability and biocompatibility. After reaching this goal{,} in vitro experiments were performed with selected nanomaterials to investigate the potential of engineered MNP-RBC constructs in theranostic approaches.