Magnetic Aggregation‐Induced Bone‐Targeting Nanocarrier with Effects of Piezo1 Activation and Osteogenic–Angiogenic Coupling for Osteoporotic Bone Repair

Abstract Osteoporosis, characterized by an imbalance in bone homeostasis, is a global health concern. Bone defects are difficult to heal in patients with osteoporosis. Classical drug treatments for osteoporotic bone defects have unsatisfactory efficacy owing to side effects and imprecise delivery problems. In this study, a magnetic aggregation‐induced bone‐targeting poly(lactic‐co‐glycolic acid, PLGA)‐based nanocarrier (ZOL‐PLGA@Yoda1/SPIO) is synthesized to realize dual‐targeted delivery and precise Piezo1‐activated therapy for osteoporotic bone defects. Piezo1 is an important mechanotransducer that plays a key role in regulating bone homeostasis. To achieve dual‐targeting properties, ZOL‐PLGA@Yoda1/SPIO is fabricated using zoledronate (ZOL)‐decorated PLGA, superparamagnetic iron oxide (SPIO), and Piezo1‐activated molecule Yoda1 via the emulsion solvent diffusion method. Bone‐targeting molecular mediation and magnetic aggregation‐induced properties can jointly and effectively achieve precise delivery to localized bone defects. Moreover, Yoda1 loading enables targeted and efficient mimicking of mechanical signals and activation of Piezo1. Experiments in vivo and in vitro demonstrate that ZOL‐PLGA@Yoda1/SPIO can activate Piezo1 in bone defect areas of osteoporotic mice, improve osteogenesis through YAP/β‐catenin signaling axis, promote a well‐coordinated osteogenesis–angiogenesis coupling, and significantly accelerate bone reconstruction within the defects without noticeable side effects. Overall, this novel dual‐targeting nanocarrier provides a potentially effective strategy for the clinical treatment of osteoporotic bone defects.