Hypoxia‐ and pH‐Responsive Metal‐Phenolic Network‐Engineered Ferroptosis‐Immuno Microspheres for Transarterial Chemoembolization in Hepatocellular Carcinoma

Abstract Drug‐eluting microspheres (DEMs) are extensively utilized in transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), but their drug‐loading and release capacities remain suboptimal. Moreover, the hypoxic and immunosuppressive microenvironment induced by embolization hampers treatment efficacy and prognosis. To overcome these challenges, engineered DEMs incorporating a metal‐phenolic network (MPN) is developed, exhibiting dual hypoxia‐ and pH‐responsiveness tailored to the tumor microenvironment. This approach leverages ferroptosis‐immune synergy to improve TACE‐based HCC treatment. The hypoxia‐activated prodrug TH302 is integrated into these modified DEMs, enabling targeted hypoxia‐responsive therapy against residual hypoxic tumor cells post‐embolization. The MPN, composed of tannic acid (TA), Fe 3+ , and Mn 2+ , improves TH302 loading efficiency and ensures controlled pH‐responsive drug release. Additionally, the MPN reverses immunosuppression within the tumor microenvironment, triggering a ferroptosis‐immune cascade. This approach not only demonstrates efficacy in treating embolized tumors but, when combined with a PD‐L1 inhibitor, reduces distant non‐embolized liver tumors. This integrated approach represents a significant advancement in TACE, improving therapeutic efficacy and clinical outcomes in the management of HCC.