While magnetic nanoparticles offer exciting possibilities for stem cell imaging or tissue bioengineering, their long-term intracellular fate remains to be fully documented. Besides, it appears that magnetic nanoparticles can occur naturally in human cells, but their origin and potentially endogenous synthesis still need further understanding. In an effort to explore the life cycle of magnetic nanoparticles, we investigated their transformations upon internalization in mesenchymal stem cells and as a function of the cells’ differentiation status (undifferentiated, or undergoing adipogenesis, osteogenesis, and chondrogenesis). Using magnetism as a fingerprint of the transformation process, we evidenced an important degradation of the nanoparticles during chondrogenesis. For the other pathways, stem cells were remarkably “remagnetized” after degradation of nanoparticles. This remagnetization phenomenon is the direct demonstration of a possible neosynthesis of magnetic nanoparticles in cellulo and could lay some foundation to understand the presence of magnetic crystals in human cells. The neosynthesis was shown to take place within the endosomes and to involve the H-subunit of ferritin. Moreover, it appeared to be the key process to avoid long-term cytotoxicity (impact on differentiation) related to high doses of magnetic nanoparticles within stem cells. Significance Naturally occurring magnetic nanoparticles have been detected in human cells; however, their origin and role remain unknown. In the present paper, the observation of long-term transformations of man-made magnetic nanoparticles internalized in human stem cells displays a mechanism regarding their assimilation. Indeed, the nanoparticles are first degraded by the stem cells, and then new magnetic nanoparticles are synthesized in situ from the released iron. This “remagnetization” phenomenon is observed under specific pathways only, involves the ferritin protein, and seems linked to a detoxification mechanism in case of iron excess. It also brings a direct experimental proof that magnetic nanoparticles can be synthesized by human cells.

Magnetic nanoparticles offer versatile opportunities for anti-cancer therapy, stemming from a single metal element, iron, naturally processed by the human body. Applications range from magnetic hyperthermia to the emerging fields of photothermal therapy and ferroptosis induction.

A polymer coating with multiple binding sites provides iron oxide nanoparticles with protection against intracellular degradation.

The use of magnetic nanoparticles in nanomedicine keeps expanding and, for most applications, the nanoparticles are internalized in cells then left within, bringing the need for accurate, fast, and easy to handle methodologies to assess their behavior in the cellular environment. Herein, a benchtop-size magnetic sensor is introduced to provide real-time precise measurement of nanoparticle magnetism within living cells. The values obtained with the sensor, of cells loaded with different doses of magnetic nanoparticles, are first compared to conventional vibrating sample magnetometry (VSM), and a strong correlation remarkably validates the use of the magnetic sensor as magnetometer to determine the nanoparticle cellular uptake. The sensor is then used to monitor the progressive intracellular degradation of the nanoparticles, over days. Importantly, this real-time in situ measure is performed on a stem cell-spheroid tissue model and can run continuously on a same spheroid, with cells kept alive within. Besides, such continuous magnetic measurement of cell magnetism at the tissue scale does not impact either tissue formation, viability, or stem cell function, including differentiation and extracellular matrix production.