Self-Assembly Albumin Nanoparticles for Improved Anticancer Effect and Reinforced Ferroptosis in Metastatic Colorectal Cancer Treatment

Ferroptosis, a newly recognized mode of regulated cell death characterized by iron-mediated accumulation of lipid peroxides, represents a viable treatment strategy for metastatic colorectal cancer (CRC). Nonetheless, the clinical effectiveness of single-agent ferroptosis inducers is constrained by the adaptive and self-repair capabilities of tumor cells. To address this limitation, this study proposes a self-amplifying ferroptosis nanodrug SOR/QUE@HSA, which is engineered by coencapsulating sorafenib (SOR) and quercetin (QUE) within human serum albumin (HSA). SOR/QUE@HSA offers a uniform structure, improved stability, and enhanced drug delivery efficiency. The released SOR and QUE impeded the uptake of glutamine (Gln) and cysteine (Cys) by targeting solute carrier family 7 member 11 (SLC7A11) and solute carrier family 1 member 5 (SLC1A5), respectively. This dual inhibition consequently disrupts the synthesis of glutathione (GSH), resulting in a marked downregulation of glutathione peroxidase 4 (GPX4), ultimately enhancing ferroptosis in CRC. Additionally, QUE inhibits hexokinase-II (HK-II), which results in decreased ATP production and lactate (LA) generation, thereby impeding tumor metastasis. In summary, our findings unveil a plausible role for the therapeutic potential of QUE as a ferroptosis-inducing anticancer agent, and the synergistic combination of QUE and SOR within this nanoplatform presents an option for treating metastatic CRC.