Sun Yujun, Wu Haoyu, Chen Junxi, Xue Chunyu, Luo Jiankai, Wu Jionglin, Li Shixun, Li Changchuan, Liu Taihe, Pan Chenhao, Ding Yue
Department of Orthopeadic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P. R. China.
ACS Biomater Sci Eng. 2025 Aug 11;11(8):4725-4736. doi: 10.1021/acsbiomaterials.5c00306. Epub 2025 Jul 11.
Small extracellular vesicles (sEVs) from human umbilical-cord-derived mesenchymal stem cells (UCMSCs) hold promise for cartilage regeneration in osteoarthritis (OA). However, their therapeutic effectiveness is significantly limited by rapid clearance through blood and lymphatic vessels in the synovial tissue after intra-articular injection. This study aimed to enhance the chondrocyte-targeting ability and improve the cartilage repair potential of UCMSC-derived sEVs by conjugating them with a chondrocyte-affinity peptide (CAP) using copper-free click chemistry. The targeting ability and therapeutic effects of these CAP-modified sEVs (CAP-sEVs) were evaluated and . CAP-sEVs exhibited enhanced chondrocyte targeting and greater retention within the articular cavity compared to nonmodified sEVs. In IL-1β-stimulated chondrocytes, CAP-sEVs significantly reduced the expression of matrix-degrading enzymes while increasing collagen type II synthesis, demonstrating superior therapeutic effects. Animal experiments further confirmed that CAP-sEVs had good biocompatibility, delayed articular cartilage degradation, and reduced subchondral bone loss in early stage OA. These findings suggest that CAP-sEVs represent a novel and promising strategy for OA treatment and provide an innovative drug delivery system for targeted cartilage therapy.
人脐带间充质干细胞（UCMSC）来源的小细胞外囊泡（sEV）有望用于骨关节炎（OA）的软骨再生。然而，关节腔内注射后，它们通过滑膜组织中的血管和淋巴管快速清除，其治疗效果受到显著限制。本研究旨在通过使用无铜点击化学将UCMSC来源的sEV与软骨细胞亲和肽（CAP）偶联，增强其对软骨细胞的靶向能力，并提高其软骨修复潜力。对这些CAP修饰的sEV（CAP-sEV）的靶向能力和治疗效果进行了评估。与未修饰的sEV相比，CAP-sEV表现出增强的软骨细胞靶向能力和在关节腔内的更长保留时间。在白细胞介素-1β刺激的软骨细胞中，CAP-sEV显著降低了基质降解酶的表达，同时增加了II型胶原蛋白的合成，显示出优异的治疗效果。动物实验进一步证实，CAP-sEV具有良好的生物相容性，延缓了早期OA关节软骨的降解，并减少了软骨下骨丢失。这些发现表明，CAP-sEV是一种新型且有前景的OA治疗策略，并为靶向软骨治疗提供了一种创新的药物递送系统。
