Sequentially Regulated Lysosomal Assembly Formation and Degradation for Potent Inflammasome Driven Immunotherapy

Abstract Inflammasome‐mediated in situ cancer vaccines hold promise for cancer immunotherapy but are hampered by poor specificity to the tumor microenvironment (TME) and inadequate antigen‐specific immune responses. Here, sequentially regulated transmutable nanoparticles ( _PEG CSMP NPs) are developed to enhance NLRP3 inflammasome activity and induce chemodynamic therapy (CDT) for robust adjuvant and antigens effects. Copper–manganese silicate nanoparticles (CSM NPs) are functionalized with molybdenum polyoxometalate (POM) clusters and ROS‐cleavable poly(ethylene glycol) (mPEG) to form _PEG CSMP NPs. Upon exposure to high ROS levels in the TME, _PEG CSMP NPs shed their PEG layer, triggering aggregation and lysosomal rupture in dendritic cells (DCs) to activate the NLRP3 inflammasome. Meanwhile, high glutathione (GSH) levels in tumor cells degrade the aggregated particles, releasing metal ions that induce CDT to damage tumor cells and release tumor‐associated antigens (TAAs). This dual mechanism of lysosomal assembly formation and degradation enhances antigen presentation and T cell activation for precise cancer immunotherapy.