Zhang Weijun, Zhang Ye, Hao Zhengan, Yao Pengjie, Bai Jinwu, Chen Hongyu, Wu Xiaoyong, Zhong Yuliang, Xue Deting
Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, PR China; Clinical Research Center of Motor System Disease of Zhejiang Province, PR China.
Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, China.
J Control Release. 2025 Feb 10;378:306-319. doi: 10.1016/j.jconrel.2024.12.017. Epub 2024 Dec 18.
Postmenopausal osteoporosis is a common degenerative disease, with suboptimal clinical outcomes. The targets of current therapeutic agents are both nonspecific and diverse. We synthesized a novel nanoparticle (NP), ALN@BMSCM@PLGA-TK-PEG-SS31. After intravenous injection, the NP evaded immune phagocytosis, targeted bone tissue, and efficiently downregulated bone reactive oxygen species (ROS) generation. The core PLGA-TK-PEG-SS31 NP was ∼100 nm in diameter. The TK chemical bond breaks on exposure to ROS, releasing the novel mitochondrion-targeting peptide SS31. Outer bone marrow mesenchymal stem cell membranes (BMSCMs) were used to coat the NP with surface proteins to ensure membrane functionality. The circulation time was prolonged and immune phagocytosis was evaded. Embedding the DSPE-PEG-ALN lipid within the cell membrane enhanced the bone-targeting ability of the NP. Our results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 exerted dual effects on bone tissue in vitro, significantly inhibiting RANKL-induced osteoclastogenesis in the presence of HO and promoting osteogenic differentiation in BMSCs. In a mouse model of ovariectomy-induced osteoporosis, ALN@BMSCM@PLGA-TK-PEG-SS31 significantly ameliorated oxidative stress and increased bone mass with no notable systemic side effects. These results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 is a promising treatment for osteoporosis.
绝经后骨质疏松症是一种常见的退行性疾病，临床疗效欠佳。目前治疗药物的靶点既非特异性的，又多种多样。我们合成了一种新型纳米颗粒（NP），即ALN@BMSCM@PLGA-TK-PEG-SS31。静脉注射后，该纳米颗粒可逃避免疫吞噬，靶向骨组织，并有效下调骨活性氧（ROS）的生成。核心的PLGA-TK-PEG-SS31纳米颗粒直径约为100纳米。TK化学键在接触ROS时断裂，释放出新型线粒体靶向肽SS31。外层骨髓间充质干细胞膜（BMSCMs）用于用表面蛋白包裹纳米颗粒，以确保膜的功能。延长了循环时间并逃避了免疫吞噬。将DSPE-PEG-ALN脂质嵌入细胞膜可增强纳米颗粒的骨靶向能力。我们的结果表明，ALN@BMSCM@PLGA-TK-PEG-SS31在体外对骨组织发挥双重作用，在有HO存在的情况下显著抑制RANKL诱导的破骨细胞生成，并促进骨髓间充质干细胞的成骨分化。在卵巢切除诱导的骨质疏松症小鼠模型中，ALN@BMSCM@PLGA-TK-PEG-SS31显著改善氧化应激并增加骨量，且无明显的全身副作用。这些结果表明，ALN@BMSCM@PLGA-TK-PEG-SS31是一种有前景的骨质疏松症治疗方法。
