Ultrasound-Induced Valence Varying of Single-Atom Fe in Sub-Nanospiral Alternating Heterostructures for Tumor Pyroptosis and Immunotherapy

Abstract Inducing pyroptosis converts immunosuppressive “cold tumors” to immunogenic “hot tumors” for immunotherapy, yet unregulated pyroptosis may cause systemic inflammation and tumor metastasis. Here, we report single Fe atoms anchored on NiOxSy-phosphomolybdic acid (PMA) sub-1 nm spiral alternating heterostructures (Sub-NSPs) for ultrasound (US)-boosting reactive oxygen species (ROS) generation to induce controlled pyroptosis and metastasis immunotherapy. Sub-nanoscale electron delocalization renders the Fe and Mo elements in intermediate valence states, which provides a basis for the reversible redox processes that deplete glutathione (GSH) and trigger chemodynamic therapy (CDT) in the tumor microenvironment (TME). Notably, the unique curled structure significantly reduces hydrogen peroxide (H2O2) activation energy, promotes CDT-mediated hydroxyl radical (•OH) generation, and enhances oxygen (O2) generation to alleviate hypoxia. Additionally, the alternating heterostructures act as “compartments” of different charges, separating US-excited electrons and holes effectively to amplify singlet oxygen (1O2) yield for sonodynamic therapy (SDT). More importantly, under US, the atomically dispersed FeII converted from FeIII maximizes the production capacity of •OH. Consequently, Sub-NSPs induce over 50-fold higher US-triggered ROS and the abundant and distinct ROS together with GSH depletion synergistically provokes mitochondrial oxidative stress, activating caspase-1/GSDMD axis to induce pyroptosis for the metastasis immunotherapy.