Institute of Molecular Medicine (IMM), Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Institute of Functional Nano & Soft Materials Laboratory (FUNSOM), Soochow University, Suzhou, Jiangsu 215123, China.
Sci Adv. 2023 Aug 2;9(31):eadf3329. doi: 10.1126/sciadv.adf3329.
Current clinical approaches to osteoporosis primarily target osteoclast biology, overlooking the synergistic role of bone cells, immune cells, cytokines, and inorganic components in creating an abnormal osteoporotic microenvironment. Here, metal-polyDNA nanoparticles (Ca-polyCpG MDNs) composed of Ca and ultralong single-stranded CpG sequences were developed to reconstruct the osteoporotic microenvironment and suppress osteoporosis. Ca-polyCpG MDNs can neutralize osteoclast-secreted hydrogen ions, provide calcium repletion, promote remineralization, and repair bone defects. Besides, the immune-adjuvant polyCpG in MDNs could induce the secretion of osteoclastogenesis inhibitor interleukin-12 and reduce the expression of osteoclast function effector protein to inhibit osteoclast differentiation, further reducing osteoclast-mediated bone resorption. PPi generated during the rolling circle amplification reaction acts as bisphosphonate analog and enhances bone targeting of Ca-polyCpG MDNs. In ovariectomized mouse and rabbit models, Ca-polyCpG MDNs prevented bone resorption and promoted bone repair by restoring the osteoporotic microenvironment, providing valuable insights into osteoporosis therapy.
目前骨质疏松症的临床治疗方法主要针对破骨细胞生物学，而忽略了骨细胞、免疫细胞、细胞因子和无机成分在创建异常骨质疏松微环境中的协同作用。在这里，开发了由钙和超长单链 CpG 序列组成的金属多聚 DNA 纳米颗粒（Ca-多聚 CpG MDN），以重建骨质疏松微环境并抑制骨质疏松症。Ca-多聚 CpG MDN 可以中和破骨细胞分泌的氢离子，提供钙补充，促进再矿化，并修复骨缺损。此外，MDN 中的免疫佐剂多聚 CpG 可以诱导破骨细胞生成抑制剂白细胞介素-12 的分泌，并降低破骨细胞功能效应蛋白的表达，从而抑制破骨细胞的分化，进一步减少破骨细胞介导的骨吸收。滚环扩增反应产生的焦磷酸根作为双膦酸盐类似物，增强了 Ca-多聚 CpG MDN 的骨靶向性。在去卵巢小鼠和兔模型中，Ca-多聚 CpG MDN 通过恢复骨质疏松微环境来防止骨吸收并促进骨修复，为骨质疏松症治疗提供了有价值的见解。
