Cholesterol-mediated endoplasmic reticulum targeting to enhance the immune-activating capability of doxorubicin for hepatocellular carcinoma.

Severe endoplasmic reticulum stress (ERS) activates ER autophagy and related apoptotic pathways, promoting cell death, a characteristic that has been applied in cancer treatment. Targeted delivery of immunogenic cell death (ICD) inducers, such as doxorubicin (DOX), to the ER can significantly enhance ERS and induce ICD in cells, thereby activating the body's anti-tumor immune response and effectively killing cancer cells. Based on the cholesterol metabolism and intracellular transport characteristics of Hepatocellular carcinoma (HCC) cells, this study designed a nanoparticle delivery system using cholesterol phosphate conjugates (CHP) as carriers for the delivery of DOX (DOX@HCCP). The results show that DOX@HCCP exhibits an endocytosis pathway similar to that of cholesterol, characterized by a high dependence on energy. The endocytosis pathways primarily involve caveolin-mediated endocytosis, macropinocytosis, and clathrin-mediated endocytosis, followed by lysosomal escape to the ER via the cholesterol-mediated intracellular transport pathway. The targeted delivery of DOX to the ER induces strong ERS, effectively triggers cell apoptosis, and promotes ICD, significantly activating the body's anti-tumor immune response, thereby enhancing the anti-tumor effects.