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.