Drug-Delivery Nanoplatform with Synergistic Regulation of Angiogenesis–Osteogenesis Coupling for Promoting Vascularized Bone Regeneration

作者：Yahong Li, Junjin Zhu, Xin Zhang, Yuanyuan Li, Shu Zhang, Linxin Yang, Ruyi Li, Qianbing Wan, Xibo Pei, Junyu Chen, Jian Wang · 发表于：ACS Applied Materials & Interfaces · 年份：2023 · DOI：10.1021/acsami.2c23107 · 被引用次数：125 · 研究领域：Bone Tissue Engineering Materials、Connective tissue disorders research、Cancer, Hypoxia, and Metabolism

It has been confirmed that substantial vascularization is an effective strategy to heal large-scale bone defects in the field of bone tissue engineering. The local application of deferoxamine (DFO) is among the most common and effective methods for promoting the formation of blood vessels, although its short half-life in plasma, rapid clearance, and poor biocompatibility limit its therapeutic suitability. Herein, zeolitic imidazolate framework-8 (ZIF-8) was selected as a vehicle to extend the half-life of DFO. In the present study, a nano DFO-loaded ZIF-8 (DFO@ZIF-8) drug delivery system was established to promote angiogenesis–osteogenesis coupling. The nanoparticles were characterized, and their drug loading efficiency was examined to confirm the successful synthesis of nano DFO@ZIF-8. Additionally, due to the sustained release of DFO and Zn 2+, DFO@ZIF-8 NPs were able to promote angiogenesis in human umbilical vein endothelial cells (HUVECs) culture and osteogenesis in bone marrow stem cells (BMSCs) in vitro. Furthermore, the DFO@ZIF-8 NPs promoted vascularization by enhancing the expression of type H vessels and a vascular network. The DFO@ZIF-8 NPs promoted bone regeneration in vivo by increasing the expression of OCN and BMP-2. RNA sequencing analysis revealed that the PI3K-AKT-MMP-2/9 and HIF-1α pathways were upregulated by DFO@ZIF-8 NPs in HUVECs, ultimately leading to the formation of new blood vessels. In addition, the mechanism by which DFO@ZIF-8 NPs promoted bone r...