Spatial‐Constraint Modulation of Intra/Extracellular Reactive Oxygen Species by Adaptive Hybrid Materials for Boosting Pyroptosis and Combined Immunotherapy of Breast Tumor

Abstract Pyroptosis‐immunotherapy has potential for triple‐negative breast cancer treatment, but its efficacy is limited by insufficient pyroptosis activation and the need for phased, balanced, and spatially controlled activation of active species during long‐term treatment. To reconcile intracellular/extracellular demands in tumor ablation, a nanoparticle‐hydrogel hybrid enabling spatiotemporal reactive oxygen species (ROS) modulation is engineered. An open‐shell sonosensitizer with unpaired electrons in its molecular orbitals is prepared by chelating Cu 2 ⁺ with TCPP. These sonosensitizers are undergoing bovine serum albumin mediated biomineralization to form calcium phosphate particles and are incorporated into an injectable hydrogel through Schiff base crosslinking between dopamine‐functionalized oxidized hyaluronic acid and gallic acid‐modified chitosan. After intratumoral injection, nanoparticles endocytosed into tumor cells undergo acidic degradation, releasing calcium ions and GSH‐activatable sonosensitizers. Calcium overload synergizes with ultrasound‐mediated oxidative stress to induce mitochondrial damage and pyroptosis, while adhesive hydrogels retained in the extracellular matrix control excessive secondary ROS levels to protect oxidation‐sensitive entities. This dual‐action mechanism enhances the overall therapeutic effect by combining immediate tumor killing with long‐term immune activation. This study provides a new route to hybrid material design, addressing the conflicting demands of short‐term tumor ablation and long‐term immune activation, overcoming the limitations of current pyroptosis‐based immunotherapies.