Xing Yuyuan, Hu Yanhui, Zhang Xiao, Zheng Diwei, Ma Guanghui, Diao Yanyan, Yue Hua, Wei Wei, Zhang Suojiang
Beijing Key Laboratory of Solid State Battery and Energy Storage Process, State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, P. R. China.
College of Chemical and Engineering, University of Chinese Academy of Sciences, Beijing, P. R. China.
Nat Commun. 2025 Jul 28;16(1):6929. doi: 10.1038/s41467-025-62206-x.
While ionic liquids (ILs) have diverse applications, their potential in biomedical applications remains largely untapped due to gaps in systematic understanding of the spectrum of IL biosafety (biocompatibility/toxicity). Here, we establish an IL library and identify an in vitro reduction in biocompatibility (increased toxicity) with increased ILs' cationic alkyl chain length. Particularly, we present compelling evidence for IL nanoaggregates in aqueous environment, thereby elucidating the mechanisms involved in cell interactions. ILs with short cationic alkyl chains (scILs) are restricted in intracellular vesicles, whereas ILs with long cationic alkyl chains (lcILs) accumulate to the mitochondria for inducing mitophagy and apoptosis. The occurrence of dysfunctional behaviour in lcILs is also observed in vivo, with a positive correlation between the lcIL signal in tissues and mitophagy/apoptotic levels. Irrespective of the administration routes (oral/intramuscular/intravenous), scILs exhibit ~30-80 times greater tolerance than lcILs. The feasibility of scIL nanoaggregates as carriers for insoluble drugs is thus validated, and an enhanced bioavailability over the commercial tablet is acquired. The findings obtained by integrating computational analysis with diverse cell/animal evaluations (from multiple cell lines, cell spheroids, patient-derived organoids to male murine and canine models) offer unique insights into the behaviour, mechanisms, and biomedical application scenarios of IL nanoaggregates.
虽然离子液体（ILs）有多种应用，但由于对IL生物安全性（生物相容性/毒性）范围的系统理解存在差距，其在生物医学应用中的潜力在很大程度上尚未得到开发。在此，我们建立了一个IL文库，并确定随着IL阳离子烷基链长度的增加，其体外生物相容性降低（毒性增加）。特别地，我们提供了关于IL在水环境中纳米聚集体的有力证据，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的IL（scILs）被限制在细胞内囊泡中，而具有长阳离子烷基链的IL（lcILs）则在线粒体中积累，从而诱导线粒体自噬和细胞凋亡。在体内也观察到lcILs出现功能失调行为，组织中的lcIL信号与线粒体自噬/凋亡水平之间呈正相关。无论给药途径（口服/肌肉注射/静脉注射）如何，scILs的耐受性比lcILs高约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，并获得了比市售片剂更高的生物利用度。通过将计算分析与多种细胞/动物评估（从多个细胞系、细胞球、患者来源的类器官到雄性小鼠和犬模型）相结合而获得的研究结果，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。
