Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation

作者：Mengxing Zhang, Jing Li, Na Ji, Qixue Bao, Ningyun Sun, Hongding Rong, Peng Xu, Lan Yang, Mingxin Xie, Shanshan He, Qing Lin, Zhirong Zhang, Lin Li, Ling Zhang · 发表于：Nano Letters · 年份：2023 · DOI：10.1021/acs.nanolett.3c03569 · 被引用次数：1 · 研究领域：MXene and MAX Phase Materials、Extracellular vesicles in disease、RNA Interference and Gene Delivery

In recent years, live-cell-based drug delivery systems have gained considerable attention. However, shear stress, which accompanies blood flow, may cause cell death and weaken the delivery performance. In this study, we found that reducing cholesterol in macrophage plasma membranes enhanced their tumor targeting ability by more than 2-fold. Our study demonstrates that the reduced cholesterol level deactivated the mammalian target of rapamycin (mTOR) and consequently promoted the nuclear translocation of transcription factor EB (TFEB), which in turn enhanced the expression of superoxide dismutase (SOD) to reduce reactive oxygen species (ROS) induced by shear stress. A proof-of-concept system using low cholesterol macrophages attached to MXene (e.g., l-RX) was fabricated. In a melanoma mouse model, l-RX and laser irradiation treatments eliminated tumors with no recurrences observed in mice. Therefore, cholesterol reduction is a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.