Nanoparticles with intermediate hydrophobicity polarize macrophages to plaque-specific Mox phenotype via Nrf2 and HO-1 activation.

Mox macrophages were identified recently and are closely associated with atherosclerosis. Considering the potential health risks and the impact on macrophage modulation, this study investigated the Mox polarization of macrophages induced by nanoparticles (NPs) with tunable hydrophobicity. One nanoparticle (C4NP) with intermediate hydrophobicity efficiently upregulated the mRNA expression of Mox-related genes including HO-1, Srxn1, Txnrd1, Gsr, Vegf and Cox-2 through increased accumulation of Nrf2 at a nontoxic concentration in both resting and LPS-challenged macrophages. Additionally, C4NP impaired phagocytic capacity by 20% and significantly increased the secretion of cytokines, including TNFα, IL-6 and IL-10. Mechanistic studies indicated that intracellular reactive oxygen species (ROS) were elevated by 1.5-fold and 2.6-fold in resting and LPS-challenged macrophages respectively. Phosphorylated p62 was increased by 2.5-fold in resting macrophages and maintained a high level in LPS-challenged ones, both of which partially accounted for the significant accumulation of Nrf2 and HO-1. Notably, C4NP depolarized mitochondrial membrane potential by more than 50% and switched macrophages from oxidative phosphorylation-based aerobic metabolism to glycolysis for energy supply. Overall, this study reveals a novel molecular mechanism potentially involving ROS-Nrf2-p62 signaling in mediating macrophage Mox polarization, holding promise in ensuring safer and more efficient use of nanomaterials.