Xylopic acid (XA), a diterpene kaurene and the major active ingredient of the African spice Xylopia aethiopica (Annonaceae), is reported to possess anti-inflammatory and analgesic properties. Here, we investigated the therapeutic potential of XA for rheumatoid arthritis (RA), a debilitating autoimmune inflammatory disease characterized by joint damage, in the complete Freund's adjuvant (CFA)-induced arthritis model in rats. We synthesized bioinspired reconstituted high-density lipoprotein (rHDL) nanoparticles loaded with purified XA crystals (rHDL/XA) that passively accumulate in inflamed joints of CFA-induced arthritic rats. Treatment with rHDL/XA minimized mononuclear cell infiltration of CFA-induced arthritic sites and ameliorated disease burden. Metabolomic and transcriptomic analyses revealed that the major molecular pathways perturbed following CFA-induced arthritis correlated with amino acid and lipid metabolism, which were restored to normal states by rHDL/XA treatment. This work demonstrates the anti-RA potential of XA in a nanoformulation and uncovers its underlying therapeutic mechanisms at the transcript and metabolite levels.

木糖二酸（XA），二萜烯天花烯和非洲香料Xylopia aethiopica的主要活性成分（Annonaceae），据报道具有抗炎和止痛作用。在这里，我们在完整的弗氏佐剂（CFA）诱导的大鼠关节炎模型中研究了XA对类风湿性关节炎（RA）的治疗潜力，类风湿性关节炎是一种以关节损伤为特征的衰弱性自身免疫性炎性疾病。我们合成了生物启发的重组高密度脂蛋白（rHDL）纳米粒子，其中负载有纯化XA晶体（rHDL / XA），该晶体被动积聚在CFA诱发的关节炎大鼠的发炎关节中。用rHDL / XA治疗可将CFA诱导的关节炎部位的单核细胞浸润降至最低，并减轻疾病负担。代谢组学和转录组学分析表明，CFA诱发的关节炎后干扰的主要分子途径与氨基酸和脂质代谢有关，通过rHDL / XA处理可将其恢复到正常状态。这项工作证明了XA在纳米制剂中的抗RA潜力，并揭示了其在转录本和代谢产物水平上的潜在治疗机制。