Bone-targeted Mn₃O₄ nanozymes alleviate osteoporosis by remodeling the age-related oxidative stress microenvironment

Osteoporosis has become a significant chronic disease, threatening human health as the population ages. It is characterized by oxidative stress resulting from abnormal osteoclast activity, decreased osteoblast activity, and local vascular rupture, which leads to hypoxia in the bone microenvironment. Mn₃O₄ nanozymes show superior superoxide dismutase and catalase efficiency because of the high ratio of Mn²⁺ and Mn³⁺, which allows them to scavenge ROS and alleviate hypoxia. In this study, we developed bone-targeting Mn₃O₄@ZOL nanozymes with a 6 to 8 nm particle size, demonstrating excellent antioxidant properties. These nanozymes reduce intracellular reactive oxygen species levels, alleviate cellular hypoxia, and promote autophagy-associated osteogenic differentiation in mesenchymal stem cells, restoring their ability to differentiate into osteogenic cells. Furthermore, they inhibit osteoclast differentiation and improve vascularization in human umbilical vein endothelial cells. In vivo, the Mn₃O₄@ZOL nanozymes effectively reduce oxidative stress, promote osteogenic differentiation, facilitate angiogenesis, and inhibit osteoclast formation. Meanwhile, Mn₃O₄@ZOL nanozymes effectively promote bone remodeling and exhibit adequate biosafety. This research provides insights into the mechanisms by which Mn₃O₄@ZOL nanozymes can be utilized for osteoporosis treatment, establishing a theoretical and experimental basis for their development.