AML‐Targeted Metal‐Polyphenol Nanoplatform Induces Ferroptosis‐ICD Cascade for Antitumor Immunity Boosting

Acute myeloid leukemia (AML) remains a therapeutic challenge due to its low immunogenicity and immunosuppressive tumor microenvironment (iTME). We developed a ferritin-based nanoplatform (Fe-SH@Fn) co-delivering shikonin (SH) and Fe³⁺ to synergistically induce ferroptosis and activate immunogenic cell death (ICD). Ferritin, a ligand for CD71, which is overexpressed on AML cells, enables tumor targeting and encapsulates Fe-SH formed by coordination between SH and Fe³⁺. In AML cells, high intracellular glutathione triggers Fe-SH@Fn disassembly: Fe³⁺ reduces to Fe²⁺ to drive Fenton reaction-mediated ferroptosis, while SH induces ICD. This dual effect boosts the release of damage-associated molecular patterns, remodeling the microenvironment by promoting dendritic cell maturation, enhancing CD8⁺ T cell infiltration, and reducing regulatory T cells. In vivo, Fe-SH@Fn achieved 81.25% tumor growth inhibition in subcutaneous AML model and extended median survival by 2.8-fold in orthotopic AML model without systemic toxicity. This work presents a translatable strategy that overcomes AML immunosuppression through targeted drug delivery and synergistic ferroptosis-ICD activation.