Breaking Age‐Impaired Bone Healing Challenge: Smart Hydrogel‐Coated Implant Reprograms Aging Bone Microenvironments via Senolytic and Pro‐Angiogenic Dual Therapy

In the aging microenvironment, the decreased ability of bone regeneration seriously affects the efficiency of bone defect repair. To address this, a smart, reactive oxygen species (ROS)-responsive hydrogel-coated titanium implant loaded with copper-dihydromyricetin nanoparticles (CuDHM NPs) is developed. This implant synergistically modulates the bone repair microenvironment through dual mechanisms: anti-senescence and pro-angiogenesis. The hydrogel coating enables sustained, responsive release of CuDHM under oxidative stress conditions linked to cellular senescence. This mechanism effectively scavenges excessive intracellular and extracellular ROS accumulation, restores mitochondrial metabolic function, and directly decelerates the senescence of mesenchymal stem cells (MSCs). Moreover, the material induces the upregulation of key signaling molecules such as vascular endothelial growth factor (VEGF), promotes the formation of type H vessels, and synergistically ameliorates MSCs' senescence by modulating the extracellular matrix microenvironment. Notably, the formation of type H vessels itself enhances bone tissue regeneration. In vivo animal experiments demonstrate that the material accelerates bone repair by restoring local microenvironmental homeostasis and promoting vascularization. In summary, this study presents a novel implant that reprograms the microenvironment to combat age-related bone healing issues by addressing both cellular senescence and poor vascularization, offering a promising strategy for enhanced recovery in elderly patients with strong clinical potential.