Multifunctional Fe-melatonin nanozyme facilitates osteoporotic bone regeneration based on a mitochondrial protection and microenvironment remodeling strategy

The vicious cycle of oxidative stress and mitochondrial dysfunction constitutes the critical driver for the imbalance of bone homeostasis in osteoporosis. Excessive reactive oxygen species (ROS) not only directly damage bone marrow-derived mesenchymal stem cells (BMSCs) by impairing mitochondrial function but also trigger persistent inflammatory responses. These factors synergistically lead to the pathological bone microenvironment of osteoporosis, severely hindering bone regeneration process, thereby causing difficulty in osteoporotic bone repair. Herein, we developed Fe-melatonin nanozymes (Fe-Mel NZs), which inhibit excessive oxidative stress by efficiently eliminating ROS, rescue mitochondrial dysfunction, and thereby suppress inflammatory responses and restore the bone microenvironment homeostasis. In vitro experiments demonstrated that Fe-Mel NZs exhibited superoxide dismutase and catalase-like catalytic activities to efficiently scavenge ROS, restore mitochondrial homeostasis, and promote osteogenic differentiation in BMSCs. Meanwhile, Fe-Mel NZs guided macrophages toward M2 polarization, reduced the pro-inflammatory cytokine production, and increased the anti-inflammatory cytokine levels by eliminating excessive ROS, showing a significant regulatory effect on the immune microenvironment, thereby accelerating the bone repair process. Most notably, in vivo evaluations showed that the Fe-Mel NZs significantly promoted osteoporotic bone regeneration. Moreover, high-throughput sequencing results demonstrated that the nanozymes exerted effective therapeutic effects by activating the AMPK signaling pathway, further normalizing the osteoporotic bone microenvironment. Overall, this research presents a nanozyme based on a mitochondrial protection and microenvironment remodeling dual-regulation strategy and offers critical perspective into the development and application of iron-based nanozymes as a potential therapeutic approach for osteoporotic bone repair and other oxidative stress-related diseases.