Iron Oxide Nanoparticles Induce Autophagosome Accumulation through Multiple Mechanisms: Lysosome Impairment, Mitochondrial Damage, and ER Stress

Magnetite (iron oxide, Fe3O4) nanoparticles have been widely used for drug delivery and magnetic resonance imaging (MRI). Previous studies have shown that many metal-based nanoparticles including Fe3O4 nanoparticles can induce autophagosome accumulation in treated cells. However, the underlying mechanism is still not clear. To investigate the biosafety of Fe3O4 and PLGA-coated Fe3O4 nanoparticles, some experiments related to the mechanism of autophagy induction by these nanoparticles have been investigated. In this study, the results showed that Fe3O4-Fe3O4, PLGA-coated Fe3O4, and PLGA nanoparticles could be taken up by the cells through cellular endocytosis. Fe3O4 nanoparticles extensively impair lysosomes and lead to the accumulation of LC3-positive autophagosomes, while PLGA-coated Fe3O4 nanoparticles reduce this destructive effect on lysosomes. Moreover, Fe3O4 nanoparticles could also cause mitochondrial damage and ER and Golgi body stresses, which induce autophagy, while PLGA-coated Fe3O4 nanoparticles reduce the destructive effect on these organelles. Thus, the Fe3O4 nanoparticle-induced autophagosome accumulation may be caused by multiple mechanisms. The autophagosome accumulation induced by Fe3O4 was also investigated. The Fe3O4, PLGA-coated Fe3O4, and PLGA nanoparticle-treated mice were sacrificed to evaluate the toxicity of these nanoparticles on the mice. The data showed that Fe3O4 nanoparticle treated mice would lead to the extensive accumulation of autophagosomes in the kidney and spleen in comparison to the PLGA-coated Fe3O4 and PLGA nanoparticles. Our data clarifies the mechanism by which Fe3O4 induces autophagosome accumulation and the mechanism of its toxicity on cell organelles and mice organs. These findings may have an important impact on the clinical application of Fe3O4 based nanoparticles.