Magnetic-driven Interleukin-4 internalization promotes magnetic nanoparticle morphology and size-dependent macrophage polarization

Macrophages are known to depict two major phenotypes: classically activated macrophages (M1), associated with high production of pro-inflammatory cytokines, and alternatively activated macrophages (M2), which present an anti-inflammatory function. A precise control over M1-M2 polarization is a promising strategy in therapeutics to modulate both tissue regeneration and tumor progression processes. However, this is not a simple task as macrophages behave differently depending on the microenvironment. In agreement with this, non -consistent data have been reported regarding macrophages response to magnetic iron oxide nanoparticles (MNPs). To investigate the impact of both tissue microenvironment and MNPs properties on the obtained macrophage responses, single-core (SC) and multi-core (MC) citrate coated MNPs, are synthesized and, after-wards, loaded with a macrophage polarization trigger, IL-4. The developed MNPs are then tested in macrophages subjected to different stimuli. We demonstrate that macrophages treated with low concentrations of MNPs behave differently depending on the polarization stage independently of the concentration of iron. Moreover, we find out that MNPs size and morphology determines the effect of the IL-4 loaded MNPs on M1 macrophages, since IL-4 loaded SC MNPs favor the polarization of M1 macrophages towards M2 phenotype, while IL-4 loaded MC MNPs further stimulate the secretion of pro-inflammatory cytokines.