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

Kelei Wang, Xiayu Hu, Changfen Bi, Yimai Zhuang, Yu Zhang, Zhenxuan Shao, Liang Chen, Haibing Xiang, Lingxiao Jin, Shixin Chen, Haochen Mou, Yucheng Xue, Fangqian Wang, Shenzhi Zhao, Xupeng Chai, Zilong Li, Miaojie Fang, Yiwen Xu, Yuwen Wang, Zeqi Zhou, Ning Zhang, Luntao Liu, Zhaoming Ye, Zengjie Zhang

Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China. · pubmed

Paper

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.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

The study demonstrates that a nanoparticle-based proton-coupled electron transfer system can restore mitochondrial function and promote bone regeneration in aged mice by targeting bioenergetic insufficiency. This work is relevant as it addresses mitochondrial dysfunction, a hallmark of aging, but represents an incremental preclinical advance in a specific tissue context with limited immediate translational impact on lifespan or broad age-related pathology.

Author of this paper? Send a correction.