Iron Homeostasis-Regulated Adaptive Metabolism of PEGylated Ultrasmall Iron Oxide Nanoparticles

Iron oxide nanoparticles have become increasingly significant in the biomedical field due to their exceptional magnetic properties and biocompatibility. However, understanding their <i>in vivo</i> metabolism and transformation is crucial due to the potential biological effects they may induce. This study investigates the metabolic pathways of PEGylated ultrasmall iron oxide nanoparticles (PUSIONPs) <i>in vivo</i>, particularly under varying iron statuses and dosages. Employing a comprehensive analytical approach─including magnetic resonance imaging, elemental analysis, histological assessments, hematological analysis, and Western blot analysis─the biodistribution and transformation of PUSIONPs were mapped. The findings reveal significant differences in the metabolic fate of PUSIONPs between iron-sufficient and iron-deficient conditions, underscoring the pivotal role of iron homeostasis in regulating PUSIONPs biodegradation. In iron-deficient states, degradation and transformation were markedly accelerated, with the released iron rapidly incorporated into hemoglobin. Additionally, the liver and spleen exhibited different PUSIONPs metabolism rates due to their distinct physiological roles: the spleen, primarily responsible for iron recycling, facilitated faster degradation, while the liver, serving as an iron storage organ, showed slower degradation. Under iron deficiency, most degradation products were directed toward hemoglobin synthesis, whereas under normal conditions, the liver gradually metabolized the degradation products, and the spleen retained higher iron levels. Moreover, PUSIONPs degradation demonstrated dose dependency, with higher doses slowing degradation and reducing the utilization rate by the iron-deficient body. Comprehensive safety evaluations confirmed that PUSIONPs exhibit excellent biocompatibility across all doses, with no significant safety concerns. Compared to the clinically used intravenous iron supplement iron sucrose, PUSIONPs also demonstrated superior bioavailability and more effective iron supplementation. These findings provide critical insights into the interaction between iron oxide nanoparticles and iron metabolism, offering a foundation for future research and the broader application of PUSIONPs in biomedical contexts.