Mitochondria-targeted, Single-atom Nanozymes Accelerate Bone Regeneration by Augmenting Stem Cell Energy Metabolism

Critical-sized bone defects (CSBDs) do not heal spontaneously throughout a patient’s lifetime, posing a global challenge to musculoskeletal health. Resident stem cells in bone, which are indispensable in skeletal development and regeneration, undergo enhanced mitochondrial activities during osteogenic differentiation. However, accumulation of excessive reactive oxygen species (ROS) produced by injured bone tissues can lead to mitochondrial damage, which negatively affects the osteogenic differentiation of stem cells. In such an environment, it is crucial to target mitochondria in stem cells to remove ROS and restore mitochondrial homeostasis. Herein, we developed a dendritic mesoporous silica nanoparticle (DMSN)-based single-atom nanozyme, named TPP-DMSN-Fe/Cu, loaded with Fe and Cu single atoms and modified with mitochondrion-targeting triphenylphosphonium (TPP). In vitro , TPP-DMSN-Fe/Cu nanozymes were found to upregulate stem cell osteogenesis by scavenging ROS, enhancing mitochondrial function by fatty acid oxidation, and promoting autophagy of abnormal mitochondria. The nanozymes also augmented mitochondrial biogenesis via the CaMKK/AMPK/PGC-1α pathway. In vivo , TPP-DMSN-Fe/Cu nanozymes significantly enhanced mitochondrial biogenesis and bone regeneration, leading to increased bone volume and mineral density at the sites of CSBDs in rats. Taken together, these findings show that the multifunctional, mitochondria-targeting TPP-DMSN-Fe/Cu nanozymes hold promising potential in accelerating bone regeneration via regulation of cellular energy metabolism.