Deng Yasi, Li Bin, Zheng Hao, Liang Ling, Yang Yupei, Liu Shiqi, Wang Mengyun, Peng Caiyun, Liu Bin, Wang Wei, Yu Huanghe
TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Materia Medica Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha 410208, China.
Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, School of Pharmacy, Changsha Medical University, Changsha 410219, China.
Asian J Pharm Sci. 2025 Jun;20(3):101037. doi: 10.1016/j.ajps.2025.101037. Epub 2025 Feb 22.
Abnormal activation of macrophages and osteoclasts (OCs) contributes significantly to rheumatoid arthritis (RA) development by secretion of numerous inflammatory factors. Notably, these cells exhibit significant upregulation of folate receptor proteins on their surfaces. Unfortunately, there is a current lack of safe and effective therapeutic drugs for RA. Xuetongsu (XTS), a triterpenoid compound extracted from Roxb Craib, has demonstrated the ability to significantly inhibit the proliferation of RA fibroblast-like synoviocytes (RAFLS). However, its clinical application is hampered by poor targeting and short half-life. To address these drawbacks, we previously developed a nano-drug system named HRPS nanoparticles (NPs), which effectively targets RAFLS and inhibits synovial hyperplasia. However, this system overlooked the essential role of OCs in RA-related bone destruction. Therefore, we designed a novel folate-modified biomimetic Prussian blue (PB)-XTS NP (FMPX NP) for the selective delivery of XTS into inflammatory macrophages and OCs. The NP exhibits an excellent photothermal effect when assisted by laser irradiation, facilitating targeted release of XTS within inflammatory macrophages and OCs. The synergistic anti-inflammatory and reactive oxygen species scavenging effects of PB NPs and XTS are mediated by the inhibition of the NF-κB signaling pathway in inflammatory macrophages and RANK/RANKL/NFATc1 signaling pathway in OCs. experiments showed that FMPX NPs extended the half-life of XTS by 2.32 times, decreased hind foot swelling from 12.10 ± 0.49 mm to 8.24 ± 0.09 mm in the model group, and prevented bone damage. In conclusion, this study introduces a novel dual-targeted nano-based therapy for RA joints and highlights its potential for biochemical photothermal triple therapy for RA. FMPX NPs inhibit arthritis-related inflammation and bone destruction through a dual-target strategy, providing new insights for targeted drug therapies in clinical RA treatment.
巨噬细胞和破骨细胞（OCs）的异常激活通过分泌多种炎症因子，在类风湿性关节炎（RA）的发展中起重要作用。值得注意的是，这些细胞表面的叶酸受体蛋白显著上调。不幸的是，目前缺乏用于RA的安全有效的治疗药物。雪通素（XTS）是从毛瓣金花中提取的一种三萜类化合物，已证明其能够显著抑制RA成纤维样滑膜细胞（RAFLS）的增殖。然而，其临床应用受到靶向性差和半衰期短的阻碍。为了解决这些缺点，我们之前开发了一种名为HRPS纳米颗粒（NPs）的纳米药物系统，它能有效靶向RAFLS并抑制滑膜增生。然而，该系统忽视了OCs在RA相关骨破坏中的重要作用。因此，我们设计了一种新型的叶酸修饰的仿生普鲁士蓝（PB）-XTS纳米颗粒（FMPX NP），用于将XTS选择性递送至炎性巨噬细胞和OCs。在激光照射辅助下，该纳米颗粒表现出优异的光热效应，促进XTS在炎性巨噬细胞和OCs内的靶向释放。PB NPs和XTS的协同抗炎和活性氧清除作用是通过抑制炎性巨噬细胞中的NF-κB信号通路和OCs中的RANK/RANKL/NFATc1信号通路介导的。实验表明，FMPX NPs使XTS的半衰期延长了2.32倍，模型组后足肿胀从12.10±0.49毫米降至8.24±0.09毫米，并预防了骨损伤。总之，本研究介绍了一种用于RA关节的新型双靶点纳米疗法，并突出了其在RA生化光热三联疗法中的潜力。FMPX NPs通过双靶点策略抑制关节炎相关的炎症和骨破坏，为临床RA治疗中的靶向药物治疗提供了新的见解。
