Wang Yaping, Wang Jingrong, Ma Mengze, Gao Rui, Wu Yan, Zhang Chuangnian, Huang Pingsheng, Wang Weiwei, Feng Zujian, Gao Jianbo
Medical 3D Printing Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China.
Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
Biomater Res. 2024 Jun 18;28:0046. doi: 10.34133/bmr.0046. eCollection 2024.
The occurrence of rheumatoid arthritis (RA) is highly correlated with progressive and irreversible damage of articular cartilage and continuous inflammatory response. Here, inspired by the unique structure of synovial lipid-hyaluronic acid (HA) complex, we developed supramolecular HA-nanomedicine hydrogels for RA treatment by mediating macrophage-synovial fibroblast cross-talk through locally sustained release of celastrol (CEL). Molecular dynamics simulation confirmed that HA conjugated with hydrophobic segments could interspersed into the CEL-loaded [poly(ε-caprolactone--1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(ε-caprolaone--1,4,8-trioxa[4.6]spiro-9-undecanone] (PECT) nanoparticles to form the supramolecular nanomedicine hydrogel HA-poly(ε-caprolactone--1,4,8-trioxa[4.6]spiro-9-un-decanone)/PECT@CEL (HP@CEL), enabling fast hydrogel formation after injection and providing a 3-dimensional environment similar with synovial region. More importantly, the controlled release of CEL from HP@CEL inhibited the macrophage polarization toward the proinflammatory M1 phenotype and further suppressed the proliferation of synovial fibroblasts by regulating the Toll-like receptor pathway. In collagen-induced arthritis model in mice, HP@CEL hydrogel treatment substantial attenuated clinical symptoms and bone erosion and improved the extracellular matrix deposition and bone regeneration in ankle joint. Altogether, such a bioinspired injectable polymer-nanomedicine hydrogel represents an effective and promising strategy for suppressing RA progression through augmenting the cross-talk of macrophages and synovial fibroblast for regulation of chronic inflammation.
类风湿关节炎（RA）的发生与关节软骨的进行性和不可逆损伤以及持续的炎症反应高度相关。在此，受滑膜脂质 - 透明质酸（HA）复合物独特结构的启发，我们通过雷公藤红素（CEL）的局部持续释放介导巨噬细胞 - 滑膜成纤维细胞相互作用，开发了用于RA治疗的超分子HA - 纳米药物水凝胶。分子动力学模拟证实，与疏水链段共轭的HA可以穿插到负载CEL的[聚（ε - 己内酯 - 1,4,8 - 三氧杂[4.6]螺 - 9 - 十一烷酮） - 聚（乙二醇） - 聚（ε - 己内酯 - 1,4,8 - 三氧杂[4.6]螺 - 9 - 十一烷酮）]（PECT）纳米颗粒中，形成超分子纳米药物水凝胶HA - 聚（ε - 己内酯 - 1,4,8 - 三氧杂[4.6]螺 - 9 - 十一烷酮）/PECT@CEL（HP@CEL），注射后能够快速形成水凝胶，并提供与滑膜区域相似的三维环境。更重要的是，CEL从HP@CEL中的控释抑制了巨噬细胞向促炎M1表型的极化，并通过调节Toll样受体途径进一步抑制了滑膜成纤维细胞的增殖。在小鼠胶原诱导性关节炎模型中，HP@CEL水凝胶治疗显著减轻了临床症状和骨侵蚀，并改善了踝关节的细胞外基质沉积和骨再生。总之，这种受生物启发的可注射聚合物 - 纳米药物水凝胶代表了一种通过增强巨噬细胞和滑膜成纤维细胞的相互作用来调节慢性炎症从而抑制RA进展的有效且有前景的策略。
