Cholesterol Laundry of Cell Membrane and Fatty Liver by Detergent Liposomes to Improve Anti‐Cancer Drug Responsiveness of Patient Liver Tissues

ABSTRACT Cholesterol accumulation in the plasma membrane hinders cellular drug uptake, which often limits therapeutic effects on hepatocellular carcinoma (HCC). This study aimed to develop a liposomal strategy based on its proven clinical biosafety, well‐known membrane trafficking behavior, and potential to act as membrane cholesterol‐specific detergents. Addition of cholesterol or detergent (Triton X‐100) into liposomal membranes laundered cell membrane cholesterol equivalently, thereby improving cellular uptake of drug molecules. However, only the detergent‐containing liposomes caused cytotoxicity as liposomal concentrations increased, justifying the use of cholesterol (+)‐liposomes. The hypoxic status of patient HCCs elevated lipidation, which was laundered by liposomal treatment. Consequent drug uptake and therapeutic effects were improved in cancer cells, 3D spheroids, and patient‐derived HCC tissues using perfusion‐based 3D chip systems. Uptake of hydrophobic drug was also improved to a greater extent compared to hydrophilic ones across these models. In mouse fatty livers, IV injection of cholesterol (+)‐liposomes alone decreased hepatic lipidation, inflammation, and fibrosis. When the plasma membrane forms endosomes by encapsulating the liposomes after uptake, membrane cholesterol is transferred from the endosomes to the liposomes and subsequently metabolized in the endoplasmic reticulum (ER). This mechanism was validated using endosome‐mimetic nanovesicles and biochemical ER regulators. The results indicate the promising potential of cholesterol (+)‐liposomes to improve HCC therapy.