Folic acid (FA) is one of the most widely utilized small-molecule ligands for cancer targeted drug delivery. Natural IgM was recently found to avidly absorb on the surface of FA-functionalized liposomes (FA-sLip), negatively regulating the in vivo performance by efficiently activating complement. Herein, FA-functionalized lipodiscs (FA-Disc) were constructed to successfully circumvent IgM-mediated opsonization and retained binding activity with folate receptors in vivo. The FA moiety along with the bound IgM was restricted to the highly curved rim of lipodiscs, leading to IgM incapability of presenting the membrane-bound conformation to trigger complement activation. The C1q docking, C3 binding, and C5a release were blocked and accelerated blood clearance phenomenon was mitigated of FA-Disc. FA-Disc retained folate binding activity and could effectively target folate receptor positive tumors in vivo. The present study provides a useful solution to avoid the negative regulation by IgM and achieve FA-enabled targeting by exploring disc-shaped nanocarriers.

中文翻译：

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叶酸通过规避 IgM 介导的调理作用来实现脂质盘的靶向递送

叶酸（FA）是用于癌症靶向药物递送的最广泛使用的小分子配体之一。最近发现天然 IgM 会在 FA 功能化脂质体 (FA-sLip) 的表面大量吸收，通过有效激活补体负调节体内性能。本文构建了 FA 功能化脂盘 (FA-Disc) 以成功规避 IgM 介导的调理作用并在体内保留与叶酸受体的结合活性. FA 部分与结合的 IgM 一起被限制在脂盘的高度弯曲边缘，导致 IgM 无法呈现膜结合构象以触发补体激活。FA-Disc 的 C1q 对接、C3 结合和 C5a 释放被阻断，加速血液清除现象得到缓解。FA-Disc 保留了叶酸结合活性，可有效靶向体内叶酸受体阳性肿瘤。本研究提供了一种有用的解决方案，可以避免 IgM 的负调控，并通过探索盘形纳米载体实现 FA 靶向。