Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils
Shield and sword nano-soldiers ameliorate rheumatoid arthritis by multi-stage manipulation of neutrophils
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DOI：
10.1016/j.jconrel.2021.05.008
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发表时间：
2021-05-15
影响因子：
10.8
通讯作者：
He, Qin
中科院分区：
文献类型：
--
作者：
Li, Jiaxin;Long, Yang;He, Qin
风湿性关节炎（RA）的特征是炎症的爆发。中性粒细胞是炎症爆发的罪魁祸首，是第一个被招募到发炎关节的炎性细胞，并通过刺激趋化因子的释放来促进自身的招募。在这里，基于中性粒细胞，用LMWH-TOS纳米颗粒（LT NPs）建立了一种新的“盾牌和剑士兵”策略。低分子量肝素（LMWH）是一种亲水性片段，通过与炎症内皮细胞表面的P-选择素结合，抑制粘附级联反应，从而阻断中性粒细胞的跨血管运动。协同地，MMP-9（其由募集的嗜中性粒细胞分泌并降解关节软骨的主要组分）被疏水片段d-α-生育酚琥珀酸酯（TOS）减少，起到剑的作用。在胶原诱导的关节炎（CIA）小鼠模型中，LT纳米粒显示出显著的靶向作用，包裹一线抗RA药物甲氨蝶呤后，显示出显著的治疗效果。我们的工作证明了中性粒细胞的多阶段操作是可行和有效的，为RA的治疗提供了一个新的概念。
Rheumatoid arthritis (RA) is characterized by the outbreak of inflammation. Neutrophils, the main culprit of the outbreak of inflammation, are the first inflammatory cells to be recruited to inflamed joints and facilitate the recruitment of themselves by stimulating the release of chemokines. Here, based on neutrophils, a novel antiinflammatory "shield and sword soldiers" strategy is established with LMWH-TOS nanoparticles (LT NPs). The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium. Synergistically, MMP-9, which is secreted by the recruited neutrophils and degrade the main component of articular cartilage, is reduced by the hydrophobic fragment d-alpha-tocopheryl succinate (TOS), functioning as a sword. In collagen-induced arthritis (CIA) mouse model, LT NPs show significant targeting effect, and exhibit prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. Our work proves that the multi-stage manipulation of neutrophils is feasible and effective, providing a new concept for RA treatment.