Delivery of MiR335-5p-Pendant Tetrahedron DNA Nanostructures Using an Injectable Heparin Lithium Hydrogel for Challenging Bone Defects in Steroid-Associated Osteonecrosis
Delivery of MiR335-5p-Pendant Tetrahedron DNA Nanostructures Using an Injectable Heparin Lithium Hydrogel for Challenging Bone Defects in Steroid-Associated Osteonecrosis
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DOI：
10.1002/adhm.202101412
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发表时间：
2021-11-01
影响因子：
10
通讯作者：
Kang, Pengde
中科院分区：
文献类型：
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作者：
Li, Donghai;Yang, Zhouyuan;Kang, Pengde
皮质类固醇诱导的Dickkopf-1（DKK 1）上调和Wnt信号转导抑制导致骨代谢紊乱和类固醇相关性骨坏死（SAON）。植入生物材料来调节Wnt通路是修复SAON相关的挑战性骨缺损的一种有前途的方法。在这里，四面体DNA纳米结构（TDNs）被制造为基因载体，以递送靶向DKK 1翻译的MiR 335 - 5 p。合成肝素锂水凝胶（Li-hep-gel）以充当锂和MiR@TDNs递送剂。最后，在体内评估使用MiR@TDNs/Li-hep-gel复合物对SAON中挑战性骨缺损的修复效果。结果表明，MiR@TDNs被骨髓间充质干细胞（BMSC）吸收，并增加细胞活力和减少凋亡。MiR@TDNs可促进碱性磷酸酶表达和钙结节沉积，降低BMSCs脂滴表达，促进血管内皮生长因子分泌和血管样结构形成。将MiR@TDNs/Li-hep-gel植入SAON模型后，骨坏死的内部骨缺损得到修复，大面积的新骨伴随着新生血管和减少的空骨陷窝。总之，MiR@TDNs/Li-hep-gel可提供锂和MiR@TDNs的双重递送，其协同上调Wnt信号传导通路，增强挑战性骨缺损中的骨再生，并且可潜在地用于SAON修复。
Corticosteroids-induced Dickkopf-1 (DKK1) upregulation and Wnt signaling inhibition result in bone metabolism disorder and steroid-associated osteonecrosis (SAON). Implanting biomaterials to regulate the Wnt pathway is a promising method to repair challenging bone defects associated with SAON. Here, tetrahedral DNA nanostructures (TDNs) are fabricated as gene carriers to deliver MiR335-5p, which targets DKK1 translation. Heparin lithium hydrogel (Li-hep-gel) is synthesized to act as a lithium and MiR@TDNs delivery agent. Finally, the repair effects on challenging bone defect in SAON using a MiR@TDNs/Li-hep-gel composite are assessed in vivo. The results reveal that MiR@TDNs are absorbed by bone mesenchymal stem cells (BMSCs) and increase cell viability and reduce apoptosis. Moreover, MiR@TDNs promote alkaline phosphatase expression and calcium nodular deposition, decrease lipid droplet expression of BMSCs, and improve vascular endothelial growth factor secretion and vascular-like structure formation in vitro. After MiR@TDNs/Li-hep-gel is implanted into the SAON model, the internal bone defect of osteonecrosis is repaired with a large area of new bone accompanied with neovascularization and reduced empty lacunae. In conclusion, MiR@TDNs/Li-hep-gel can provide dual delivery of lithium and MiR@TDNs, which synergistically upregulate the Wnt signaling pathway, enhancing bone regeneration in challenging bone defects, and can be potentially used in SAON repair.