RATIONALE Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease. OBJECTIVE Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule. METHODS AND RESULTS Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of -15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P=9.95122×10-6). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice. CONCLUSIONS We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.

中文翻译：

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载有雷帕霉素的仿生纳米颗粒可逆转血管炎症。

理由通过雷帕霉素通过仿生药物递送系统的局部递送，可以减少血管炎症，从而减少血管疾病的进展。目的使用仿生纳米颗粒将雷帕霉素递送至血管壁，以在较短的给药时间表后减轻动脉粥样硬化体内模型中的炎症。方法和结果使用从活化的J774巨噬细胞中纯化的膜蛋白合成了仿生纳米颗粒（白体）。使用动态光散射对负载雷帕霉素的纳米颗粒进行表征，发现其直径为108±2.3 nm，表面电荷为-15.4±14.4 mV，多分散指数为0.11 + / 0.2。为了进行体内研究，给ApoE-/-小鼠喂食高脂饮食12周。给小鼠注射PBS，游离雷帕霉素（5 mg / kg），或载有雷帕霉素的白细胞（Leuko-Rapa； 5 mg / kg），每天一次，共7天。在用Leuko-Rapa治疗的小鼠中，与未治疗的小鼠（30.2±13.34％）和单独的雷帕霉素（26.8±9.87％）相比，分解主动脉组织的流式细胞仪显示主动脉中的增殖巨噬细胞较少（15.6±9.79％）。在用Leuko-Rapa治疗的小鼠中，巨噬细胞增殖减少与MCP（单核细胞趋化蛋白）-1和IL（白介素）-b1水平降低相关。此外，Leuko-Rapa处理的小鼠在主动脉中的MMP（基质金属蛋白酶）活性也显着降低（平均差异2554±363.9，P = 9.95122×10-6）。在肝代谢测定中未观察到代谢或炎症标志物的显着变化。组织学分析显示肺形态有所改善，心脏，脾脏，肺，Leuko-Rapa治疗的小鼠的肝脏或肝脏。结论我们证明了仿生纳米颗粒的增殖巨噬细胞数量减少，同时关键的促炎细胞因子减少和噬菌斑形态改变。这个概念证明表明，我们的平台能够在较短的给药时间（7天）后抑制主动脉内巨噬细胞的增殖，并具有良好的毒性。这种治疗对于晚期斑块的急性稳定可能是有希望的干预措施。这个概念证明表明，我们的平台能够在较短的给药时间（7天）后抑制主动脉内巨噬细胞的增殖，并具有良好的毒性。这种治疗对于晚期斑块的急性稳定可能是有希望的干预措施。这个概念证明表明，我们的平台能够在较短的给药时间（7天）后抑制主动脉内巨噬细胞的增殖，并具有良好的毒性。这种治疗对于晚期斑块的急性稳定可能是有希望的干预措施。