Orbital hybridization-mediated nanozymes reverse cellular senescence for aged bone regeneration.

Abstract

The regeneration of aged bone is severely compromised by a deteriorating microenvironment characterized by excessive reactive oxygen species (ROS) and consequential endoplasmic reticulum stress (ERS). Herein, we report a biomimetic nanozyme engineered through synergistic p-d orbital hybridization and youthful membrane camouflage to precisely reverse this degenerative cascade. The designed Cu-Sn dual-atom core exhibits exceptional multi-enzymatic activity, scavenging superoxide anions with a 2.5-fold higher efficiency than Cu single-atom control. Mechanistic studies confirm that p-d hybridization redistributes electron density at the Sn site, lowering the energy barrier for ROS adsorption and conversion. This catalytic core is cloaked with a hybrid membrane derived from young mesenchymal stem and endothelial cells, which facilitates targeted delivery to senescent bone niches and provides intrinsic pro-regenerative signals. The composite nanozyme effectively mitigates intracellular oxidative stress and ERS in aged cells, rescuing their osteogenic and angiogenic potential. In an aged mouse model of jawbone defect, a single treatment regimen promoted robust bone regeneration, increasing the bone volume fraction (BV/TV) by 1.7-fold and significantly enhancing new bone mineralization. This work establishes a dual-principle design-orbital hybridization for catalytic amplification and youthful membrane for targeted rejuvenation-offering a versatile platform for treating a spectrum of senescence-associated diseases.