Clinical Research Center, Orthopedic Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China.
Guangdong Key Lab of Orthopedic Technology and Implant, General Hospital of Southern Theater Command of PLA, Guangzhou, Guangdong, 510010, China.
J Nanobiotechnology. 2022 Feb 19;20(1):89. doi: 10.1186/s12951-022-01297-w.
Utilization of joint-resident mesenchymal stem cells (MSC) to repair articular cartilage is a promising strategy in osteoarthritis (OA) therapy but remains a considerable research challenge. Here, hierarchical targeting and microenvironment responsive peptide functionalized nanoparticles (NPs) are used to achieve cartilage repair in situ. Ultrasmall copper oxide (CuO) NPs are conjugated with type 2 collagen and MSC dual-targeting peptide (designated WPV) with a matrix metalloproteinase 2 (MMP-2)-sensitive sequence as a spacer to achieve hierarchical targeting. Guided by this peptide, WPV-CuO NPs initially penetrate cartilage and subsequently expose the inner MSC-targeted peptide to attract MSCs through MMP-2 clearance. CuO further promotes chondrogenesis of MSCs. In an anterior cruciate ligament transection rat model, intraarticular injection of WPV-CuO NPs induces significant reduction of cartilage destruction. The therapeutic mechanism involves inhibition of the PI3K/AKT/mTOR pathway, as determined via transcriptome analysis. In conclusion, a novel therapeutic strategy for OA has been successfully developed based on localized MSC recruitment and cartilage repair without transplantation of exogenous cells or growth factors.
利用关节间充质干细胞（MSC）修复关节软骨是骨关节炎（OA）治疗的一种很有前途的策略，但仍然是一个相当大的研究挑战。在这里，采用分级靶向和微环境响应肽功能化纳米颗粒（NPs）实现原位软骨修复。超小氧化铜（CuO）NPs 与 2 型胶原和 MSC 双重靶向肽（命名为 WPV）偶联，其中基质金属蛋白酶 2（MMP-2）敏感序列作为间隔物以实现分级靶向。在该肽的引导下，WPV-CuO NPs 最初穿透软骨，随后暴露内部的 MSC 靶向肽，通过 MMP-2 清除来吸引 MSCs。CuO 进一步促进 MSC 的软骨生成。在前交叉韧带切断大鼠模型中，关节内注射 WPV-CuO NPs 可显著减少软骨破坏。通过转录组分析确定，其治疗机制涉及抑制 PI3K/AKT/mTOR 通路。总之，成功开发了一种基于局部 MSC 募集和软骨修复的 OA 新治疗策略，无需移植外源性细胞或生长因子。
