Multidimensional Regulation of Bone Marrow Niche Using Extracorporeal Shock Wave Responsive Nanocomposites for Osteoporosis Therapy

Abstract Multidimensional modulation of the bone marrow niche represents a pivotal therapeutic strategy for bone‐related disorders. However, its clinical translation remains challenging due to the inherent limitations imposed by the bone physiological barrier. Herein, a bone cavity‐targeted nanocomposite (ZCD) is developed that can respond to extracorporeal shock wave (ESW), enabling triaxial regulation by inhibiting adipogenic differentiation, promoting osteogenic differentiation, and suppressing osteoclast activity. This nanocomposite is synthesized using a comprehensive drug strategy incorporating zoledronic acid, disulfiram, and calcium ions. It can specifically target bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs). Following ESW stimulation, the system enables controlled drug release, effectively suppressing excessive osteoclast activation and enhancing osteoblast metabolic activity at adipogenic sites in osteoporosis. This microenvironment‐tailored intervention successfully restores bone metabolic equilibrium, enhances bone mineral density, and improves biomechanical performance, thereby establishing a transformative paradigm for precision medicine in metabolic osteoporosis treatment.