A Self‐Augmenting Ion‐ROS Nanogenerator for Deep‐Penetration Pyroptosis‐Driven Immunotherapy of Solid Tumors

ABSTRACT Pyroptosis holds significant potential for cancer immunotherapy by coupling tumor eradication with immune activation. However, its efficacy remains limited due to poor penetration of pyroptosis inducers and insufficient activation within tumors, primarily caused by dense extracellular matrix and elevated tumor interstitial fluid pressure (TIFP). To address these challenges, an acid‐responsive nanogenerator (CPFH) that co‐delivers Ca 2+ and reactive oxygen species (ROS) was developed to simultaneously enhance both penetration and pyroptosis induction. The nanogenerator integrates a calcium peroxide (CaO 2 ) core with a pH‐degradable polydopamine layer, Fe‐doped polyoxometalate (Fe‐POM) clusters, and hyaluronic acid (HA) targeting ligands. In the acidic tumor microenvironment (TME), CPFH releases Ca 2+ and H 2 O 2 , which initiates caspase‐3/gasdermin E (GSDME)‐mediated pyroptosis via Ca 2+ overload while also reducing TIFP through water depletion. Simultaneously, Fe‐POM catalyzes hydroxyl radical (•OH) generation via Fenton reaction and provides second near‐infrared (NIR‐II) photothermal effects, enhancing oxidative stress, disrupting mitochondrial function, and alleviating solid stress through collagen degradation. This self‐reinforcing Ca 2+ /ROS cycle amplifies GSDME activation and improves nanoparticle penetration. Consequently, robust immunogenic cell death occurs with damage‐associated molecular patterns (DAMPs) release, dendritic cell maturation, and cytotoxic T cell infiltration. In vivo, CPFH treatment achieved near‐complete tumor regression with minimal toxicity, demonstrating strong potential for solid tumor immunotherapy.