State Key Laboratory of Natural Medicines, Center of Advanced Pharmaceuticals and Biomaterials, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
School of Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
Nano Lett. 2021 Nov 24;21(22):9736-9745. doi: 10.1021/acs.nanolett.1c03664. Epub 2021 Nov 8.
Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. β-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the application of CD for removing lysosomal CCs. Here, we exploit poly-β-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to self-assemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF-ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann-Pick type C diseases with excessive cholesterol accumulation in the lysosome.
胆固醇晶体（CCs）最初在富含胆固醇的细胞的溶酶体中积累，会加重动脉粥样硬化的进展。β-环糊精（CD）是一种有效的胆固醇受体或 CC 增溶剂。然而，胆固醇的随机提取阻碍了 CD 用于去除溶酶体 CCs 的应用。在这里，我们利用多-β-环糊精（pCD）作为溶酶体 CC 增溶剂和接枝有苯并咪唑（BM）的葡聚糖硫酸盐作为 pH 敏感开关（pBM）自组装成超分子纳米组装体（pCD/pBM-SNA）。pCD/pBM-SNA 中的 CD 空腔在 pH 7.4（OFF）时可以被疏水 BM 有效地封闭。进入溶酶体后，pCD/pBM-SNA 解体，由于 BM 的质子化，CD 空腔恢复，将 CCs 溶解为游离胆固醇（ON），从而减少 CCs，最终增强胆固醇外排并促进动脉粥样硬化消退。我们的发现提供了一种“OFF-ON”策略，用于去除溶酶体 CCs，以预防动脉粥样硬化以及其他疾病，如溶酶体中胆固醇过度积累的尼曼-匹克 C 型疾病。
