Quantitative studies of the long-term fate of iron oxide nanoparticles inside cells, a prerequisite for regenerative medicine applications, are hampered by the lack of suitable biological tissue models and analytical methods. Here we propose stem cell spheroids as a tissue model to track intracellular magnetic nanoparticles transformations during long-term tissue maturation. We show that global spheroid magnetism can serve as a fingerprint of the degradation process and we evidence a near-complete nanoparticle degradation over a month of tissue maturation, as confirmed by electron microscopy. Remarkably, the same massive degradation was measured at the endosome level by single-endosome nano-magnetophoretic tracking in cell-free endosomal extract. Interestingly, this spectacular nanoparticles breakdown barely affected iron homeostasis: only the genes coding for ferritin light chain (iron loading) and ferroportin (iron export) were upregulated two-fold by the degradation process. Besides, the magnetic and tissular tools developed here allow screening the bio-stability of magnetic nanomaterials, as demonstrated with iron oxide nanocubes and nanodimers. Hence stem cells spheroids and purified endosomes are suitable models needed to monitor nanoparticle degradation in conjunction with magnetic, chemical and biological characterizations at the cellular scale, quantitatively, in the long term, in situ and in real time.