East Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China, 200120.
Department of Plastic Surgery, Shanghai Fourth People's Hospital, School of Medicine,Tongji University, Shanghai, 200434, People's Republic of China.
J Nanobiotechnology. 2023 Sep 22;21(1):341. doi: 10.1186/s12951-023-02086-9.
Osteoarthritis (OA) is a degenerative joint disease involving cartilage. Exosomes derived from Mesenchymal stem cells (MSCs) therapy improves articular cartilage repair, but subcutaneous fat (SC) stromal cells derived exosomes (MSCs-Exos), especially engineering MSCs-Exos for drug delivery have been rarely reported in OA therapy. This objective of this study was to clarify the underlying mechanism of MSCs-Exos on cartilage repair and therapy of engineering MSCs-Exos for drug delivery in OA. MSCs-Exos could ameliorate the pathological severity degree of cartilage via miR-199a-3p, a novel molecular highly enriched in MSCs-Exos, which could mediate the mTOR-autophagy pathway in OA rat model. Intra-articular injection of antagomiR-199a-3p dramatically attenuated the protective effect of MSCs-Exos-mediated on articular cartilage in vivo. Furthermore, to achieve the superior therapeutic effects of MSCs-Exos on injured cartilage, engineering exosomes derived from MSCs as the chondrocyte-targeting miR-199a-3p delivery vehicles were investigated in vitro and in vivo. The chondrocyte-binding peptide (CAP) binding MSCs-Exos could particularly deliver miR-199a-3p into the chondrocytes in vitro and into deep articular tissues in vivo, then exert the excellent protective effect on injured cartilage in DMM-induced OA mice. As it is feasible to obtain human subcutaneous fat from healthy donors by liposuction operation in clinic, meanwhile engineering MSCs-Exos to realize targeted delivery of miR-199a-3p into chondrocytes exerted excellent therapeutic effects in OA animal model in vivo. Through combining MSCs-Exos therapy and miRNA therapy via an engineering approach, we develop an efficient MSCs-Exos-based strategy for OA therapy and promote the application of targeted-MSCs-Exos for drug delivery in the future.
骨关节炎（OA）是一种涉及软骨的退行性关节疾病。间充质干细胞（MSCs）来源的外泌体治疗可改善关节软骨修复，但皮下脂肪（SC）基质细胞来源的外泌体（MSCs-Exos），特别是工程 MSCs-Exos 用于药物输送在 OA 治疗中很少报道。本研究的目的是阐明 MSCs-Exos 对软骨修复的潜在机制以及用于 OA 药物输送的工程 MSCs-Exos。MSCs-Exos 可以通过 miR-199a-3p 改善软骨的病理严重程度，miR-199a-3p 是一种在 MSCs-Exos 中高度富集的新型分子，可在 OA 大鼠模型中调节 mTOR-自噬途径。关节内注射抗 miR-199a-3p 可显著减弱 MSCs-Exos 介导的关节软骨的保护作用。此外，为了实现 MSCs-Exos 对受损软骨的优越治疗效果，研究了源自 MSCs 的工程外泌体作为软骨细胞靶向 miR-199a-3p 递送载体的体外和体内研究。软骨细胞结合肽（CAP）结合 MSCs-Exos 可以特别将 miR-199a-3p 递送到体外的软骨细胞和体内的深关节组织中，然后对 DMM 诱导的 OA 小鼠中的受损软骨发挥出色的保护作用。因为在临床上通过抽脂手术从健康供体中获得人皮下脂肪是可行的，同时将工程 MSCs-Exos 用于实现 miR-199a-3p 靶向递送到软骨细胞中，在 OA 动物模型中表现出出色的治疗效果。通过结合 MSCs-Exos 治疗和通过工程方法的 miRNA 治疗，我们开发了一种用于 OA 治疗的有效基于 MSCs-Exos 的策略，并促进了靶向-MSCs-Exos 在未来的药物输送中的应用。
