A Sodium Iron Phosphate Nanocatalyst-Regulated High-Mobility Ion Reservoir Enables Tumor-Selective Immunotherapy

Abstract

Sodium ion (Na⁺)-mediated pyroptosis has emerged as a promising strategy in ion interference therapy (IIT) for tumor treatment. However, conventional Na⁺ delivery systems suffer from off-target leakage and osmotic toxicity in normal tissues. Herein, we present the construction of a peroxidase-mimicking ion reservoir based on sodium iron phosphate (NFPP) nanocatalysts, which enables rapid and tumor-selective Na⁺ outflow through pH-gated nanocatalytic activation. NFPP maintains an “OFF” state in normal cells due to the minimal ion release induced by the catalytic inactivation. Crucially, in tumor cells, the peroxidase-like catalytic activity of NFPP is activated by the more acidic lysosome environment than that within normal cells, transitioning NFPP to an “ON” state. The optimal activity boosts the Na⁺ outward migration, resulting in intracellular Na⁺ overload that triggers the pyroptosis pathway. Conversely, the rapid Na⁺ flux amplifies the peroxidase-like catalytic activity, thus reinforcing oxidative stress and exacerbating pyroptosis. The NFPP nanoplatform can further provoke robust immune responses and provide long-term protection against tumor relapse and metastasis. This work pioneers a design strategy for constructing nanocatalysis-regulated high-mobility ion reservoirs to overcome limitations in precise ion modulation for selective tumor immunotherapy.