Rejuvenating Aged Bone Repair through Multihierarchy Reactive Oxygen Species‐Regulated Hydrogel

Abstract Aging exacerbates the dysfunction of tissue regeneration at multiple levels and gradually diminishes individual's capacity to withstand stress, damage, and disease. The excessive accumulation of reactive oxygen species (ROS) is considered a hallmark feature of senescent stem cells, which causes oxidative stress, deteriorates the host microenvironment, and eventually becomes a critical obstacle for aged bone defect repair. Till now, the strategies cannot synchronously and thoroughly regulate intracellular and extracellular ROS in senescent cells. Herein, a multihierarchy ROS scavenging system for aged bone regeneration is developed by fabricating an injectable PEGylated poly(glycerol sebacate) (PEGS‐NH₂)/poly(γ‐glutamic acid) (γ‐PGA) hydrogel containing rapamycin‐loaded poly(diselenide‐carbonate) nanomicelles (PSeR). This PSeR hydrogel exhibits highly sensitive ROS responsiveness to the local aged microenvironment and dynamically releases drug‐loaded nanomicelles to scavenge the intracellular ROS accumulated in senescent bone mesenchymal stem cells. The PSeR hydrogel effectively tunes the antioxidant function and delays senescence of bone mesenchymal stem cells by safeguarding DNA replication in an oxidative environment, thereby promoting the self‐renewal ability and enhancing the osteogenic capacity for aged bone repair in vitro and in vivo. Thus, this multihierarchy ROS‐regulated hydrogel provides a new strategy for treating degenerative diseases.