Poly-β-cyclodextrin Supramolecular Nanoassembly with a pH-Sensitive Switch Removing Lysosomal Cholesterol Crystals for Antiatherosclerosis

作者：Yan Zhang, Fanglin Gong, Yue Wu, Siyuan Hou, Lingjing Xue, Zhigui Su, Can Zhang · 发表于：Nano Letters · 年份：2021 · DOI：10.1021/acs.nanolett.1c03664 · 被引用次数：47 · 研究领域：Glycosylation and Glycoproteins Research、Lipid Membrane Structure and Behavior、Cholesterol and Lipid Metabolism

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 in vivo 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.