基于靶向肽改造的间充质干细胞用于膝骨关节炎治疗的作用机制与研究进展

Mechanism and research progress of mesenchymal stem cells modified with targeted peptides for the treatment of knee osteoarthritis

摘要:

膝骨关节炎（KOA）作为高致残性退行性关节疾病，非甾体抗炎药治疗难以逆转软骨损伤。间充质干细胞（MSCs）虽具软骨分化与免疫调节潜能，但天然MSCs的应用存在归巢效率低（<5%到达损伤区）、关节腔滞留短（<24 h）及炎症微环境下异常肥大分化（高表达Col10a1/Runx2）等主要瓶颈。该综述提出了以靶向肽工程化改造MSCs为核心策略：①靶向修饰：通过仿生学设计，采用点击化学或膜疏水插入法修饰MSCs表面，其归巢效率（局部浓度提高3倍）及滞留时间（≥7 d）均得到显著改善。②协同递送系统：整合纳米载体形成“双工程化MSCs”，同步精准调控软骨分化并重塑免疫微环境。KOA小鼠模型及人软骨外植体实验显示工程化MSCs促进软骨基质再生，改善病理评分。临床试验证实同种异体MSCs及联合疗法可缓解疼痛、改善功能并延缓进展，获《中国骨关节炎诊疗指南（2024版）》早期KOA阶梯治疗推荐。临床转化需解决靶向肽稳定性、纳米载体长期安全性及标准化问题。未来方向包括开发抗酶解肽（D-氨基酸替代）、靶向肽-外泌体无细胞疗法、AI辅助肽设计，以及建立自动化生产与多维度疗效标准，推动其成为中早期KOA的疾病修饰疗法。

Abstract:

Knee osteoarthritis (KOA), a highly disabling degenerative joint disease, cannot have its cartilage damage reversed by traditional treatments. Although mesenchymal stem cells (MSCs) possess the potential for chondrogenic differentiation and immunomodulation, native MSCs are plagued by several bottlenecks, including low homing efficiency (with less than 5% reaching the injured area), short retention time in the joint cavity (less than 24 hours), and abnormal hypertrophic differentiation (with high expression of Col10a1/Runx2) in the inflammatory microenvironment. This review proposed a core strategy of engineering MSCs with targeting peptides: Targeted modification: Through bionic design, the surface of MSCs was modified using click chemistry or membrane hydrophobic insertion methods, which significantly improved the homing efficiency (with the local concentration increased by 3-fold) and retention time (≥7 days). Synergistic delivery system: MSCs were integrated with nanocarriers to form "dual-engineered MSCs", which simultaneously and precisely regulated chondrogenic differentiation and remodeled the immune microenvironment. Preclinical studies (on osteoarthritis mice/human cartilage explants) showed that engineered MSCs promoted the regeneration of cartilage matrix and improved pathological scores. Clinical trials confirmed that allogeneic MSCs and combined therapy could relieve pain , improve function, and delay disease progression. This therapy was recommended in China's Clinical Practice Guidelines for Osteoarthritis (2024 Edition) for the stepped treatment of early-stage KOA. For clinical translation, issues such as the stability of targeting peptides, the long-term safety of nanocarriers, and standardization need to be addressed. Future directions include the development of enzyme-resistant peptides (via D-amino acid substitution), cell-free therapy based on targeting peptides and exosomes, artificial intelligence-assisted peptide design, as well as the establishment of automated production processes and multi-dimensional efficacy standards. These efforts aim to promote engineered MSCs to become a disease-modifying osteoarthritis drug for moderate-to-early-stage KOA.