手稿的源数据

虽然离子液体 （IL） 有多种应用，但由于对 IL 生物安全性（生物相容性/毒性）的系统理解存在差距，它们在生物医学应用中的潜力在很大程度上仍未得到开发。在这里，我们建立了一个 IL 文库，并确定了生物相容性的体外降低（毒性增加）与 ILs 的阳离子烷基链长度增加。特别是，我们为 IL 纳米聚集体在水性环境中提供了令人信服的证据，从而阐明了细胞相互作用所涉及的机制。具有短阳离子烷基链 （scIL） 的 IL 在细胞内囊泡中受到限制，而具有长阳离子烷基链 （lcIL） 的 IL 积累到线粒体中以诱导线粒体自噬和细胞凋亡。在体内也观察到 lcILs 中功能失调行为的发生，组织中的 lcIL 信号与线粒体自噬/凋亡水平呈正相关。无论给药途径（口服/肌肉注射/静脉注射）如何，scILs 的耐受性都是 lcILs 的 ~30-80 倍。因此，验证了 scIL 纳米聚集体作为不溶性药物载体的可行性，并且获得了比商业片剂更高的生物利用度。通过将计算分析与不同的细胞/动物评估（从多个细胞系、细胞球体、患者来源的类器官到雄性小鼠和犬类模型）相结合而获得的结果，为 IL 纳米聚集体的行为、机制和生物医学应用场景提供了独特的见解。

Although ionic liquids (ILs) have diverse applications, their potential for biomedical use remains largely unexploited due to gaps in the systematic understanding of IL biosafety, encompassing biocompatibility and toxicity. Here, we established an IL library and found that in vitro diminished biocompatibility (i.e., increased toxicity) of ILs correlates with increasing length of their cationic alkyl chains. Specifically, we provide compelling evidence for the presence of IL nanoaggregates in aqueous environments, thus clarifying the mechanisms underlying cellular interactions. ILs with short cationic alkyl chains (scILs) are sequestered within intracellular vesicles, whereas those with long cationic alkyl chains (lcILs) accumulate in mitochondria to trigger mitophagy and apoptosis. In vivo dysfunctional phenotypes induced by lcILs were also detected, and the abundance of lcILs in tissues positively correlates with the levels of mitophagy and apoptosis. Regardless of the administration route (oral, intramuscular injection, intravenous injection), the tolerance of scILs is approximately 30–80 times that of lcILs. Accordingly, the feasibility of scIL nanoaggregates as insoluble drug carriers was verified, and they exhibited higher bioavailability than commercial tablets. The results derived from integrating computational analysis with diverse cellular and animal assessments—including multiple cell lines, cell spheroids, patient-derived organoids, male mice and canine models—offer unique insights into the behavior, underlying mechanisms and biomedical application scenarios of IL nanoaggregates.