Folic acid (FA) has been extensively exploited to facilitate targeted delivery of nanomedicines by recognizing the folate receptor-α (FR-α) overexpressed in many human cancers. Unfortunately, none have been approved for clinical use yet. Here we reveal that FA functionalization induces heavy natural IgM absorption on the liposomal surface, depriving FA of receptor recognition and accelerating complement activation in vivo. FA functionalization does not enhance distribution of liposomes in FR-α-overexpressed tumors in comparison to plain liposomes (without FA), but leads to aggravated capture of liposomes by macrophages in the tumor, liver, and spleen. In addition, FA-functionalized polymeric nanoparticles are also vulnerable to natural IgM absorption. This work highlights the pivotal roles of natural IgM in regulating in vivo delivery of FA-functionalized nanomedicines. Due to the prevalent association of immune disorders and varying levels of immunoglobulins with cancer patients, extraordinary cautiousness is urged for clinical translation of FA-enabled targeted delivery systems.

中文翻译：

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叶酸功能化纳米药物的审问：血浆蛋白的调节作用重新审查。

通过认识到许多人类癌症中过表达的叶酸受体-α（FR-α），叶酸（FA）已被广泛利用以促进纳米药物的靶向递送。不幸的是，还没有一个被批准用于临床。在这里，我们揭示了FA功能化会在脂质体表面诱导大量天然IgM吸收，从而使FA丧失受体识别能力并在体内加速补体激活。与普通脂质体（不含FA）相比，FA功能化并不会增强FR-α过表达的肿瘤中脂质体的分布，但会导致巨噬细胞在肿瘤，肝脏和脾脏中对脂质体的捕获加剧。另外，FA-官能化的聚合物纳米颗粒也容易受到天然IgM吸收的影响。这项工作突出了天然IgM在调节FA功能化纳米药物的体内传递中的关键作用。由于免疫紊乱和免疫球蛋白水平的不同与癌症患者之间的普遍联系，对于具有FA功能的靶向递送系统的临床翻译，我们应格外谨慎。