A bioinspired catalytic nanoplatform for ferroptosis‐immunotherapy synergy in metastatic cancer

Abstract

Metastatic cancer remains difficult to treat due to the immunosuppressive tumor microenvironment and the absence of effective strategies to elicit durable systemic immunity. Ferroptosis, an iron‐dependent form of immunogenic cell death, holds promise but most inducers exhibit limited efficacy and poor engagement with innate immune sensing. Here, we present a bioinspired nanoplatform (MnMSN@MnP‐PEG) that co‐delivers manganese peroxidase (MnP) and Mn 2+ /Mn 3+ ions to synergistically trigger ferroptosis and activate the cGAS–STING pathway. Manganese peroxidase, inspired by its natural role in lignin degradation, directly catalyzes lipid peroxidation using tumor‐associated H 2 O 2 . The Mn 2+ ‐doped silica carrier not only ensures MnP delivery but also exhibits glutathione oxidase‐ and peroxidase‐like activities, amplifying oxidative stress and disrupting redox homeostasis. This cascade induces extensive lipid peroxidation and immunogenic ferroptosis, provoking robust innate and adaptive immune responses, including dendritic cell maturation, T cell and natural killer cell infiltration, and macrophage repolarization. Remarkably, a single intravenous injection eradicates primary tumors, suppresses distant tumor growth, and prevents pulmonary metastasis in murine models. Our study establishes a “catalytic immunotherapy” paradigm that leverages fungal enzymatic activity for systemic cancer treatment.