Biomimetic β-lapachone and hemin nanoassembly for intracellular oxidation cascade amplified ferroptosis in hepatocellular carcinoma therapy

Ferroptosis represents one of important no-apoptotic programmed cell death with over accumulation of iron- and reactive oxygen species (ROS). While its key role and trials for cancer therapy, achieving precise and potent induction ferroptosis in cancer cells with massive amplification of cellular lipid peroxidation and iron overloading, remains a significant hurdle. Herein, we developed a biomimetic red blood cell membranes (RBCM) camouflaged β-lapachone (Lap) and hemin nanoassembly (LHNPs@RBCM) as ferroptosis inducer for hepatocellular carcinoma (HCC) therapy. The RBCM endowed the nanoassembly with prolonged systemic circulation and improved tumor accumulation. After endocytosis of LHNPs@RBCM by cancer cells, the cancer-specific overexpressed NAD(P)H: quinone oxidoreductase (NQO1) converted the released Lap to ROS (e.g. O 2 . − , H 2 O 2 ) with good selectivity, while hemin reacted with H 2 O 2 and turned the less reactive H 2 O 2 into highly reactive hydroxyl radical (·OH) by Fenton reaction. These ·OH reacted with polyunsaturated fatty acids (PUFAs), triggering lethal lipid peroxides (LPO) and subsequent ferroptosis. Additionally, the ROS induced activation of the NRF2 pathway, which in turn upregulates NQO1 and heme oxygenase 1 (HO-1), creating a positive feedback loop that further elevates H 2 O 2 levels and labile iron pools. Due to the combination of classical GPX4 suppression pathway by ROS with a non-classical HO-1-mediated iron overload mechanism for ferroptosis, the LHNPs@RBCM effectively killed cancer cells in both cellular and animal models. The excellent therapeutic effect of LHNPs@RBCM demonstrated it as a transformative strategy for clinical ferroptosis-based therapy.