State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China.
Institute of Drug R&D, School of Life Science, Nanjing University, Nanjing, China.
Nat Nanotechnol. 2024 Aug;19(8):1203-1215. doi: 10.1038/s41565-024-01668-4. Epub 2024 May 13.
Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity.
营养摄取是肿瘤最显著的特征之一。然而，营养剥夺在临床上收效甚微。在戈谢病这种遗传性代谢疾病中，细胞产生的胆固醇-β-葡萄糖苷会在溶酶体中积累，导致细胞损伤。在这里，我们开发了一种纳米颗粒（AbCholB），以模拟天然脂蛋白携带的胆固醇，并在癌细胞中引发类似戈谢病的损伤。AbCholB 由苯硼酸修饰的胆固醇（CholB）和白蛋白组成。癌细胞将纳米颗粒摄取到溶酶体中，CholB 与葡萄糖反应生成类似胆固醇-β-葡萄糖苷的结构，该结构能抵抗降解并聚集形成微尺度晶体，以葡萄糖依赖的方式引发类似戈谢病的损伤。此外，mTOR 的营养感应功能受到抑制。观察到正常细胞由于竞争营养的能力逊于癌细胞而避免了严重的损伤。这项工作提供了一种仿生策略，通过利用癌细胞对营养的摄取来选择性地阻碍其代谢作用。
