A multimodal ROS logic-gated therapeutic platform disrupts the vicious cycle of senescence to promote aged bone defect repair.

Abstract

The impaired regeneration of aged individuals presents major challenges for repairing bone defects. Within the senescent microenvironment (SME), excessive reactive oxygen species (ROS), chronic inflammation, the accumulation of senescent cells and local infection form a self-reinforcing vicious cycle that hinders healing. Here, we developed a multimodal ROS logic-gated therapeutic platform by integrating magnesium- and manganese-doped bismuth oxide with oxygen vacancies nanoparticles (MMBOx) embedded in a rapamycin (Rapa)-loaded, 3D-printed hydrogel scaffold. <i>In vitro</i> study, this platform combines pH-responsive peroxidase, oxidase-like activity and photothermal-enhanced sonodynamic effects, enabling on-demand ROS generation for efficient antibacterial elimination. Simultaneously, MMBOx and the hydrogel scavenge excess ROS, while Rapa promotes cellular autophagy to remove damaged mitochondria, enhances ROS regulation, and delays stem cell senescence. Moreover, MMBOx enhances glutathione (GSH) synthesis and metabolism by modulating the Keap1-Nrf2 signaling pathway, thereby boosting the intracellular GSH pool and increasing ROS tolerance to support a more youthful cellular phenotype. <i>In vivo</i> studies confirm that this platform alleviates infection in the infected skin defect model. Furthermore, it attenuates SME-associated chronic inflammation and cellular senescence, and promotes bone regeneration in the aged rat calvarial defect model. These findings offer a promising strategy for addressing deteriorated SME and enhancing bone repair in the elderly.