Manganese-doped ceria nanoparticles modulate macrophage polarization to enhance osteogenic and angiogenic responses through redox regulation.

Osteoporosis is characterized by an imbalance in bone metabolism and reduced bone mass, with its pathogenesis closely linked to chronic inflammation and oxidative stress. These factors can promote macrophage polarization towards the bone-resorptive M1 phenotype. Targeting this pathological microenvironment, this study develops water-dispersible manganese-doped ceria nanoparticles, 40Mn-CeO2-PEG (40MC-PEG), to reduce intracellular reactive oxygen species (ROS) and modulate macrophage activation toward a bone formation supporting M2-like phenotype. The 40MC nanoparticles, approximately 3 nm in size, were synthesized via a reverse micelle method and subsequently modified with DSPE-PEG2000 to enhance their water solubility and biocompatibility. Manganese doping significantly enhances the catalase-like activity and alters the surface Ce3+/Ce4+ distribution of the material. In vitro experiments demonstrated that 40MC-PEG effectively reduced intracellular ROS levels in RAW 264.7 macrophages. This reduction is accompanied by a shift toward an M2-like phenotype, as evidenced by decreased CD86, iNOS, and TNF-α levels and increased CD206, Arg-1, and IL-10 levels. Conditioned medium derived from these macrophages promotes migration, alkaline phosphatase (ALP) activity, osteogenic gene expression, and mineralization in MC3T3-E1 cells, while enhancing migration, angiogenic gene expression, and tube formation in human umbilical vein endothelial cells (HUVECs) under oxidative stress. Antibody-neutralization experiments further support the involvement of BMP-2 and VEGF-associated paracrine signaling. Furthermore, 40MC-PEG directly mitigates oxidative stress-induced damage in both MC3T3-E1 cells and HUVECs. In summary, this study shows that the antioxidative enzyme-mimicking activity of 40MC-PEG is closely associated with reduced oxidative stress and macrophage phenotype remodeling, which together contribute to enhanced osteogenesis and angiogenesis. This work provides in vitro experimental evidence for developing nanozyme-based strategies that target oxidative stress and the osteoimmune microenvironment.