Evoking and enhancing ferroptosis of cancer stem cells by a liver-targeted and metal-organic framework-based drug delivery system inhibits the growth and lung metastasis of hepatocellular carcinoma

• RF@LA-Fe-MOF is a Fe(III)-based DDS loaded with small molecules RSL3 and iFSP1. • The lactobionic acids on RF@LA-Fe-MOF achieve liver targeting by binding to ASGPR. • In HCC cells, Fe(III) of RF@LA-Fe-MOF is reduced to Fe(II) to evoke ferroptosis. • RSL3 and iFSP1 inhibits GPX4 and FSP1, respectively, to enhance ferroptosis. • RF@LA-Fe-MOF inhibits the growth and lung metastasis of HCC in vitro and in vivo. Evoking ferroptosis of cancer cells is a useful strategy to prevent tumor growth and metastasis. However, intrinsic ferroptosis suppressors glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) compromise the efficacy of ferroptosis therapy. Herein, a Fe(III)-incorporated and metal-organic framework (MOF)-based drug delivery system is fabricated, loaded with small molecules RSL3 and iFSP1, and modified with liver-targeting ligand lactobionic acid. In hepatocellular carcinoma (HCC), Fe(III) of the as-synthesized RF@LA-Fe-MOF is reduced to Fe(II) by glutathione, initiating ferroptosis and disintegrating RF@LA-Fe-MOF to release RSL3 and iFSP1, which function as GPX4 inhibitor and FSP1 inhibitor, respectively. The simultaneous block of two ferroptosis suppressors largely enhances ferroptosis in HCC. Cell studies reveal potent proliferation-inhibiting and metastasis-blocking effects of RF@LA-Fe-MOF particularly toward HCC stem cells C5WN1, accompanied by decreased levels of GPX4 and FSP1 as well as augmented lipid peroxides accumulation. Moreover, RF@LA-Fe-MOF downregulates the expression of metastasis-associated protein Twist and alters the levels of epithelial-mesenchymal transition (EMT) related proteins. Treating subcutaneously HCC-bearing mice with RF@LA-Fe-MOF results in retarded tumor growth and prolonged life span. In an orthotopic C5WN1-bearing mice model, RF@LA-Fe-MOF shrinks tumor volume in liver and greatly inhibits tumor lung metastasis. The current work thus unprecedentedly achieves targeted induction and enhancement of ferroptosis in HCC by using a DDS containing two small-molecule ferroptosis boosters.