用作纳米药物的脂质纳米胶囊（LNC）已被开发用于增强药代动力学并减少药物的副作用，特别是对于癌症治疗。静脉注射后，LNC 具有重要的肝向性，但有关其毒性的数据很少，重复接触后的数据更少。本研究旨在评估 50 和 100 nm 大小的卸载 LNC 对 HepG2 和 HepaRG 肝细胞系的体外毒性和内化。与 100nm LNC 相比，50nm LNC 的内化速度较慢，并且与分化的 HepaRG 细胞相比，两种 LNC 对癌性 HepG2 细胞都表现出更高的毒性。在两种细胞系中，LNC 主要通过小窝蛋白介导的内吞作用内化。长期暴露后，LNC 对 HepaRG 细胞的毒性增加，但内化途径保持不变。细胞死亡研究表明与铁死亡有关，但与细胞凋亡无关。在对 HepaRG 细胞进行急性和反复暴露后，100nm LNC 显示出良好的安全性。最后，与分化的 HepaRG 细胞相比，LNC 在 HepG2 癌症模型中诱导出更显着的毒性，该毒性与更快的内化有关。这为 LNC 发挥活性药物对肝癌细胞的细胞毒性作用提供了良好的证据。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

Lipid nanocapsules (LNCs) used as nanomedicine have been developed to enhance pharmacokinetics and decrease side effects of drugs, particularly for cancer therapies. After intravenous administration, LNCs possess an important hepatic tropism however, few data exist about their toxicity and even less after repeated exposure. This study aimed to assess the in vitro toxicity and internalization of unloaded LNCs, of 50 and 100 nm size, on HepG2 and HepaRG liver cell lines. Internalization of the 50 nm LNCs was slower compared to the 100 nm LNCs and both LNCs exhibited a higher toxicity on cancerous HepG2 cells compared to differentiated HepaRG cells. LNCs were mainly internalized via caveolin-mediated endocytosis in both cell lines. Upon chronic exposure, the toxicity of LNCs on HepaRG cells increased, although the pathways of internalization remained unchanged. Cell death studies have demonstrated an involvement of ferroptosis, but not of apoptosis. After acute and repeated exposures on HepaRG cells, the 100 nm LNCs showed a good safety profile. Finally, LNCs induced a more significant toxicity associated with faster internalization in the HepG2 cancerous model than in the differentiated HepaRG cells. This provides good evidence for LNCs to potentialize the cytotoxic effects of an active drug on liver cancer cells.Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.