肿瘤的增殖和转移依赖于线粒体提供的能量。己糖激酶抑制剂洛尼达芬（LND）可抑制线粒体的活性，具有潜在的抗肿瘤药物作用。然而，LND的有限水溶性可能影响其生物医学应用。此外，高水平的谷胱甘肽（GSH）会削弱LND的抗癌效果。因此，迫切需要找到一种合适的方法来同时输送LND、降低GSH并监测癌细胞中的GSH水平。在此，合成了一个宿主聚合物β-环糊精-聚乙烯亚胺（β-CD-PEI）和一个客体聚合物葡萄糖聚合物-5-二硫-（2-硝基苯甲酸）（Dextran-SS-TNB），通过宿主-客体包合形成了LND加载的GSH响应性纳米颗粒，其中β-CD和TNB作为宿主和客体分子基团进行配对。该系统能够将LND和-SS-TNB同时输送到癌细胞中。结果表明，该输送系统能够降低GSH并提高癌细胞中的活性氧（ROS）水平，进一步引发基于LND的线粒体功能障碍和基于ROS的免疫原性细胞死亡（ICD），产生协同高效的抗癌作用。此外，-SS-TNB与GSH反应释放出TNB2-，可以作为一个可见光吸收410 nm的探针，用于监测细胞中的GSH水平。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

Tumor proliferation and metastasis rely on energy provided by mitochondria. The hexokinase inhibitor lonidamine (LND) could suppress the activities in mitochondria, being a potential antitumor drug. However, limited water-solubility of LND may hinder its biomedical applications. Besides, the cancer-killing effect of LND is compromised by the high level of glutathione (GSH) in cancer cells. Therefore, it is urgent to find a proper method to simultaneously deliver LND and deplete GSH as well as monitor GSH level in cancer cells. Herein, a host polymer β-cyclodextrin-polyethylenimine (β-CD-PEI) and a guest polymer dextran-5-dithio-(2-nitrobenzoic acid) (Dextran-SS-TNB) were synthesized and allowed to form LND-loaded GSH-responsive nanoparticles through host-guest inclusion complexation between β-CD and TNB as host and guest molecular moieties, respectively, which functioned as a system for simultaneous delivery of LND and -SS-TNB species into cancer cells. As a result, the delivery system could deplete GSH and elevate reactive oxygen species (ROS) level in cancer cells, further induce LND-based mitochondrial dysfunction and ROS-based immunogenic cell death (ICD), leading to a synergistic and efficient anticancer effect. In addition, -SS-TNB reacted with GSH to release TNB2-, which could be a probe with visible light absorption at 410 nm for monitoring the GSH level in the cells.Copyright © 2023 Elsevier Ltd. All rights reserved.