The long-term fate of superparamagnetic iron oxide nanoparticles (MNP) for biomedical applications represents a critical matter for human health. Investigations of the degradation behavior in in vivo tests are time consuming and not suitable for large series of MNP in the preclinical development. Therefore, the present study aimed to the simulation of the fate of MNP in vitro using complex artificial body fluids throughout the whole particle life cycle, to establish structure-activity relationships and to implement predictions based on the particle composition. A set of 13 MNP of about 150 nm was synthesized with different natural, synthetic and inorganic shell materials. To characterize storage stability, colloidal stability and degradation of core and shell in artificial fluids representing (cyto)-plasma and endosomes/lysosomes, dynamic light scattering, laser Doppler anemometry, differential scanning calorimetry, electron microscopy, photometric iron quantification, vibrational sample magnetometry, and infrared spectroscopy were applied. Over 28 days at 37 °C long-term storage of MNP only core oxidation occurred without changes of the core-shell system. In endosomal/lysosomal media a degradation behavior dependent on shell characteristics like biodegradability, acid/base properties, surface charge and water permeability could be observed. The degradation was shown to be temperature dependent enabling the development of an accelerated stress test protocol. An in vitro prediction model covering the whole application life cycle of MNP was established, enabling a fast and reliable preclinical testing of MNP.