Reducing cholesterol level in membrane of live macrophages improves their delivery performance by enhancing adaptation to blood shear stress

Abstract

Abstract In recent years, the live cells-based drug delivery systems have attracted much interests. However, shear stress in the blood flow may cause cell death and waken their delivery performances. In this study, we found that reducing cholesterol in macrophages enhanced its tumor targeting ability by more than 2-fold. Mechanism study indicates that the reduced cholesterol in macrophages deactivated the mammalian target of rapamycin (mTOR) and consequent promoted transcription factor EB (TFEB) nucleus translocation, which enhances the expression of superoxide dismutase (SOD) in cells to reduce reactive oxygen species (ROS) induced by the flow shear stress. A proof-of-concept system using low cholesterol macrophages attached MXene (l-RX) is thus fabricated. On melanoma mice model, tumors are eliminated with no recurrence in all mice after treated with l-RX and laser irradiation. Therefore, we develop a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.