Chondrocyte-Targeted MicroRNA Delivery by Engineered Exosomes toward a Cell-Free Osteoarthritis Therapy
Chondrocyte-Targeted MicroRNA Delivery by Engineered Exosomes toward a Cell-Free Osteoarthritis Therapy
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通过工程外泌体靶向软骨细胞的 MicroRNA 递送以实现无细胞骨关节炎治疗
DOI：
10.1021/acsami.0c10458
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发表时间：
2020-08-19
影响因子：
9.5
通讯作者：
Xia, Jiang
中科院分区：
文献类型：
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作者：
Liang, Yujie;Xu, Xiao;Xia, Jiang
靶向递送至患病细胞或组织是核酸药物成功临床使用的关键。特别是，将microRNA-140（miRNA-140，miR-140）穿过软骨的致密的非血管细胞外基质递送到软骨细胞中仍然是一个主要挑战。在这里，我们报告了靶向软骨细胞的外泌体作为将miR-140递送到软骨细胞中的载体，作为骨关节炎（OA）的新治疗方法。通过将软骨细胞亲和肽（CAP）与exosomes表面的溶酶体相关膜糖蛋白2b蛋白融合，我们获得了能够有效包裹miR-140的CAP-exosomes，其特异性地进入并将货物递送到体外软骨细胞中。与未标记的外泌体囊泡相反，CAP-外泌体在关节内注射后保留在关节中，体内扩散最小。CAP-外泌体还通过致密的中线粒体将miR-140递送到深层软骨区域，抑制软骨降解蛋白酶，并缓解大鼠模型中的OA进展，这指向了OA的潜在的基于细胞器的无细胞疗法。
Targeted delivery to the diseased cell or tissue is the key to the successful clinical use of nucleic acid drugs. In particular, delivery of microRNA-140 (miRNA-140, miR-140) into chondrocytes across the dense, nonvascular extracellular matrix of cartilage remains a major challenge. Here, we report the chondrocyte-targeting exosomes as vehicles for the delivery of miR-140 into chondrocytes as a new treatment for osteoarthritis (OA). By fusing a chondrocyte-affinity peptide (CAP) with the lysosome-associated membrane glycoprotein 2b protein on the surface of exosomes, we acquire CAP-exosomes that can efficiently encapsulate miR-140, specifically enter, and deliver the cargo into chondrocytes in vitro. CAP-exosomes, in contrast to nontagged exosome vesicles, are retained in the joints after intra-articular injection with minimal diffusion in vivo. CAP-exosomes also deliver miR-140 to deep cartilage regions through the dense mesochondrium, inhibit cartilage-degrading proteases, and alleviate OA progression in a rat model, pointing toward a potential organelle-based, cell-free therapy of OA.