Cascade Catalytic Nanozyme Amplifies Ferroptosis Immunotherapy in Bladder Cancer

ABSTRACT Immune checkpoint inhibitors have shown limited efficacy in bladder cancer due to the immunosuppressive tumor microenvironment. To address this challenge, we developed a β‐lapachone‐loaded iron‐based carbon nanozyme (C‐MIL@Lapa) that synergistically induces ferroptosis and immunogenic cell death (ICD). Carbonized MIL‐100(Fe) (C‐MIL) serves as both a drug carrier and a nanozyme with dual peroxidase and glutathione oxidase activities. In tumor cells, β‐lapachone generates endogenous H 2 O 2 via NQO1‐mediated redox cycling, which is then converted into cytotoxic hydroxyl radicals by C‐MIL. This cascade reaction causes glutathione depletion and lipid peroxidation, leading to ferroptosis. Meanwhile, ferroptotic cell death releases damage‐associated molecular patterns that trigger ICD, activating dendritic cells and CD8 + T cell‐mediated antitumor immunity. In vitro and in vivo results demonstrated that C‐MIL@Lapa significantly inhibited bladder cancer growth and remodeled the tumor immune microenvironment. This work provides a nanozyme‐based strategy for synergistic ferroptosis‐immunotherapy of bladder cancer with promising clinical potential.