Bioinspired, Mitochondria‐Targeted Single‐Atom Nanozyme Enhances Bone Regeneration by Reprogramming Stem Cell Energy Metabolism​

Abstract

ABSTRACT Normal mitochondrial function in stem cells is essential for effective bone regeneration, with mitochondrial complex IV (cytochrome c oxidase, CcO) playing a crucial role in sustaining electron transport chain activity and ATP synthesis. To address mitochondrial dysfunction associated with bone defects, we developed a dendritic mesoporous silica nanoparticle (DMSN)‐based, CcO‐mimetic nanozyme, named triphenylphosphonium (TPP)‐DMSN‐Fe/Cu. The nanozyme incorporated iron and copper single atoms to mimic the catalytic center of CcO and is modified with the mitochondria‐targeting agent TPP. In vitro, TPP‐DMSN‐Fe/Cu nanozymes colocalized with mitochondria and enhanced mitochondrial function, effectively regulating cellular energy metabolism and promoting stem cell osteogenesis. In vivo, TPP‐DMSN‐Fe/Cu nanozymes resulted in significantly enhanced bone regeneration compared to the control, resulting in a 177% increase in bone volume and a 12% increase in mineral density at critical‐sized bone defects in rats after 4 weeks of treatment. Taken together, these findings demonstrate that bioinspired, mitochondria‐targeting TPP‐DMSN‐Fe/Cu nanozymes hold strong promise for accelerating bone regeneration via regulating cellular energy metabolism.