A single-atom Zn-N-C catalyst non-invasively enhances mitochondrial proton flux to drive bone regeneration

Current approaches to enhance mitochondrial bioenergetics often require intrusion into the organelle, inevitably disrupting its native homeostasis. Protons (H⁺) establish the electrochemical gradient essential for electron transfer chain activity and ATP synthesis. Thus, facilitating H⁺ transfer represents a promising strategy to augment mitochondrial productivity. Here, we report a non-invasive strategy using a zinc single-atom catalyst (ZnSAC) that operates from the cytosol to catalyze H⁺ flux across mitochondrial membranes. Without crossing the membrane, ZnSAC accelerates the H⁺ flux, thereby enhancing the proton motive force that drives ATP synthesis. In vitro, ZnSAC potently elevated ATP levels and promoted osteogenic differentiation of bone marrow stromal cells (BMSCs). In a rat model of critical-sized mandibular defect, local delivery of ZnSAC robustly stimulated new bone formation, achieving near-complete regeneration. This catalytic strategy provides a foundation for safely modulating cellular energy in a myriad of diseases.