PCET‐Inspired Nanoparticles Enable Paired Proton‐Electron Delivery to Restore Mitochondrial Electron Transport and Regenerate Bone During Aging

Abstract

ABSTRACT Mitochondrial electron transport chain (ETC) dysfunction drives the accumulation of damaged mitochondria and bioenergetic insufficiency, contributing to cellular senescence and impaired tissue repair in aging. However, reconstituting ETC‐associated mitochondrial bioenergetics in situ to overcome this energy restriction remains challenging. In this study, a mitochondrial hydrogen‐supply system (EMHS) is developed that attenuates senescence‐associated phenotypes in the aged bone regenerative niche and promotes skeletal healing in aging via proton‐coupled electron transfer (PCET). It has been demonstrated that the active hydrogen generated by EMHS infiltrates mitochondria in senescent cells, enabling the paired delivery of proton–electron equivalents to restore ETC function. This mitochondrial functional recovery is accompanied by reduced mitochondrial reactive oxygen species (ROS) and improved oxidative phosphorylation (OXPHOS) capacity, which expands the functional mitochondrial pool. EMHS restores the osteogenic potential of bone marrow mesenchymal stem cells (BMSCs), enhances endothelial angiogenic capacity, and biases neutrophils toward a pro‐repair phenotype. Remarkably, following systemic administration, EMHS preferentially accumulates in bone and promotes bone‐vascular coupled regeneration in aged mice with bone defects. Overall, our findings introduce a small‐molecule drug‐free nanotherapeutic strategy that maintains a functional mitochondrial pool with potential to alleviate cellular aging and age‐related diseases.