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.
摘要：
骨质疏松,以骨稳态不平衡为特征，是全球健康问题。骨质疏松患者骨缺损难以愈合。由于副作用和不精确的递送问题,用于骨质疏松性骨缺损的经典药物治疗具有不令人满意的功效。在这项研究中,磁性聚集诱导的骨靶向聚（乳酸-共-乙醇酸，合成了基于PLGA）的纳米载体（ZOL-PLGA@Yoda1/SPIO），以实现双靶向递送和精确的Piezo1激活治疗骨质疏松性骨缺损。Piezo1是一种重要的机械换能器，在调节骨稳态中起着关键作用。为了实现双目标属性，ZOL-PLGA@Yoda1/SPIO使用唑来膦酸盐（ZOL）装饰的PLGA制造，超顺磁性氧化铁（SPIO），和Piezo1通过乳液溶剂扩散法激活分子Yoda1。骨靶向分子介导和磁聚集诱导的特性可以共同有效地实现对局部骨缺损的精确递送。此外，Yoda1加载能够有针对性地和有效地模拟机械信号和激活Piezo1。体内和体外实验表明，ZOL-PLGA@Yoda1/SPIO可以激活骨质疏松小鼠骨缺损区域的Piezo1，通过YAP/β-catenin信号轴促进成骨，促进良好协调的成骨-血管生成耦合，并显着加速缺损内的骨骼重建，而没有明显的副作用。总的来说,这种新型的双靶向纳米载体为临床治疗骨质疏松性骨缺损提供了潜在的有效策略。
