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扰内皮细胞的重要生物学功能并引起不良副作用。例如，单克隆抗体 273-34A 通过靶向血栓调节蛋白（一种主要在内皮细胞腔表面表达的蛋白质）与颗粒表面缀合时，能够将脂质体递送至肺内皮[ 221、222、223 、224、225 ]。_ 类似的抗体已显示出通过靶向血栓调节蛋白将纳米粒子有效地在细胞内或表面

递送至内皮细胞[ 226 ]。然而，血栓调节蛋白是Telegram 用户号码列表凝血酶的受体，与血浆蛋白 C 结合，该蛋白将凝血酶转化为抗凝酶。因此，针对血栓调节蛋白的抗体可能会干扰凝血级联并存在诱导血栓形成的风险，使得这些抗体对于纳米颗粒靶向缺乏吸引力[ 217 , 221 ]。 机械和非阳离子脂质方法 除了使用靶向配体之外，还采用了其他技术将脂质纳米颗粒递送至内

皮细胞，例如将胆固醇或非阳离子辅助脂质掺入 LNP 配方中。保诺瓦斯卡等人。最近报道，用 cKK-E12 纳米粒子配方中的氧化胆固醇替代未修饰的胆固醇，使 mRNA 向肝了五倍[185 ]。同样，Pattipeiluhu等人。据报道，在 patisiran 纳米颗粒配方中用阴离子 DSPG 替代中性 DSPC 显着增强了肝内皮细胞的转染[ 184]]。已报道的增

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Alnylam Pharmaceuticals 的咨询费；和博士。Wijngaard 和 Kallend 是药品公司的员工。没有报告与本文相关的其他潜在利益冲突。背景 在之前的一项研究中，发现单次注射 inclisiran（一种化学合成的小干扰 RNA，旨在靶向PCSK9信使 RNA）可在 84 天内持续降低健康志愿者的低密度脂蛋白 (LDL) 胆固醇水平。 方法 我们对 LDL 胆固醇水平升高的心血行了一项 2
  
期、多中心、双盲、安慰剂对照、多剂量递增试验，以皮下C级执行名单注射形式注射 inclisiran。患者被随机分配接受单剂安慰剂或 200、300 或 500 mg inclisiran 或两剂（第 1 天和 90 天）安慰剂或 100、200 或 300 mg inclisiran。主要终点是 180 天时 LDL 胆固醇水平相对于基线的变化。安全性数据可在第 210 天获得，LDL 胆固醇和

蛋白转化酶枯草杆菌蛋白酶-kexin 9 型 (PCSK9) 水平的数据可在第 240 天获得。 结果 共有 501 名患者接受了随机分组。接受 inclisiran 治疗的患者 PCSK9 和 LDL 胆固醇水平呈剂量依赖性降低。在第 180 天，单剂量 inclisiran 后 LDL 胆固醇水平的最小二乘平均降低为 27.9% 至 41.9%，两次剂量后 LDL 胆固醇水平最小二乘平均降低