Albumin Nanoparticles Co-Loaded with Dual Drugs for Enhanced Ferroptosis-Based Cancer Therapy through Modulating Cholesterol Metabolism

Ferroptosis is a form of regulated cell death driven by lipid peroxidation, in which the diffusion of lipid peroxidation substrates on the plasma membrane is hindered by lipid rafts, thereby inhibiting the ferroptosis process. Lipid rafts are microdomains composed of cholesterol, sphingolipids, and specific proteins. Notably, cholesterol acyltransferase sterol <i>O</i>-acyltransferase 1 (SOAT1) is highly expressed in various malignant tumors, where it promotes tumor cell growth by enhancing intracellular cholesterol storage. To alleviate the obstruction of ferroptosis progression by lipid rafts, we developed human serum albumin nanoparticles (HSA@Aur&Ava) for codelivery of the SOAT1 inhibitor avasimibe (Ava) and the ferroptosis inducer auranofin (Aur). Ava indirectly disrupts the structure of lipid rafts by blocking cholesterol esterification, while Aur induces ferroptosis by inhibiting thioredoxin reductase. The synergistic effect of these two agents enhances the accumulation of lipid peroxides and the occurrence of ferroptosis. Additionally, tumor cells release damage-associated molecular patterns (DAMPs), which enhance the maturation of dendritic cells (DCs) and further recruit CD8⁺ T cells, thereby activating the immune response. The nanoparticles significantly inhibit tumor progression through chemotherapy and immunotherapy, offering an insight for highly effective antitumor strategies from the standpoint of cholesterol metabolism.