Promoting ROS scavenging and osteogenic differentiation by metal–phenolic network nanoparticle-embedded microenvironment-responsive hydrogel for the repair of senile osteoporotic bone defects

Senile osteoporosis (SOP) features reduced bone density and degraded trabecular structure, primarily mediated through senescent impairment of osteoblasts that disrupts coupled bone remodeling homeostasis. This pathological process induces systemic bone resorption and localized bone destruction accompanied by architectural deterioration. Existing treatments for senile osteoporosis tend to focus on a single mechanism, making it challenging to simultaneously address bone formation deficits and oxidative stress. Herein, we developed a multifunctional nanoplatform utilizing metal-phenolic networks (MPNs), formed <i>via</i> coordination-driven assembly of kaempferol and manganese ions (Mn²⁺). Bone morphogenetic protein-2 (BMP-2) was immobilized within a MPN through electrostatic adsorption, and the resulting complex was encapsulated in a hyaluronic acid hydrogel. The system exhibited pH-responsive release kinetics in pathological acidic microenvironments: Mn²⁺ synergized with BMP-2 to markedly promote the differentiation of mesenchymal stem cells (MSCs) into osteoblasts, while kaempferol and Mn²⁺ reduced cellular aging by scavenging reactive oxygen species (ROS). <i>In vivo</i> evaluations using a geriatric osteoporotic bone defect model demonstrated significant improvements in bone mass augmentation and accelerated regeneration rates. This study shows the potential for using MPN nanoplatforms to simultaneously address bone formation deficits and elevated oxidative stress, thereby offering a promising solution for age-related osteoporotic repair.