Deciphering active biocompatibility of iron oxide nanoparticles from their intrinsic antagonism

Magnetite nanoparticles (Fe₃O₄ NPs) are a well proven biocompatible nanomaterial, which hold great promise in various biomedical applications. Interestingly, unlike conventional biocompatible materials (e.g., polyethylene glycol (PEG)) that are chemically and biologically inert in nature, Fe₃O₄ NPs are known to be catalytically active and exhibit prominent physiological effects. Herein, we report an "active", dynamic equilibrium mechanism for maintaining the cellular amenity of Fe₃O₄ NPs. We examined the effects of two types of iron oxide (magnetite and hematite) NPs in rat pheochromocytoma (PC12) cells and found that both induced stress responses. However, only Fe₂O₃ NPs caused significant programmed cell death; whereas Fe₃O₄ NPs are amenable to cells. We found that intrinsic catalase-like activity of Fe₃O₄ NPs antagonized the accumulation of toxic reactive oxygen species (ROS) induced by themselves, and thereby modulated the extent of cellular oxidative stress, autophagic activity, and programmed cell death. In line with this observation, we effectively reversed severe autophagy and cell death caused by Fe₂O₃ NPs via co-treatment with natural catalase. This study not only deciphers the distinct intrinsic antagonism of Fe₃O₄ NPs, but opens new routes to designing biocompatible theranostic nanoparticles with novel mechanisms.