Pyroptosis-Amplified Decoy Nanovesicles Orchestrate Pyroptotic Antigen Explosion and Endogenous Immune Revitalization...

Current advances in tumour immunotherapy remain constrained by inadequate cytotoxic T lymphocyte activation and the immunosuppressive tumour microenvironment. Innovative strategies are urgently required to enhance anti-tumour immune potency for clinical improvements in immunotherapy-resistant malignancies. Herein, we developed pyroptosis-amplified decoy nanovesicles (PADVs) to synergistically dismantle tumour resistance mechanisms and rejuvenate endogenous anti-tumour immunity. PADVs integrate checkpoint-neutralizing capability with precise regulation of the pyroptosis molecular switch in tumour cells, thereby initiating a sequential activation cascade that enables efficient presentation of tumour-specific antigens to the reshaped immune system. Systemically infused PADVs demonstrated dual-targeting priority towards lymph node and deep tumour tissues, reversing immunosuppression through competitive blockade of PD-1/PD-L1 and SIRPα/CD47 axes while providing co-stimulatory signals for immune reactivation. Furthermore, PADVs alleviate the epigenetic suppression of pyroptosis in tumours via cytosolic delivery of decitabine and LPS, enabling gasdermin D (GSDMD) upregulation and cleavage. This coordinated strategy reverses T cell exhaustion and triggers explosive antigen release via GSDMD-mediated membrane perforation, initiating a self-amplifying immune cascade involving dendritic cell activation, effector and memory T cell formation. Consequently, PADVs demonstrate excellent efficacy in suppressing tumour progression, recurrence, and metastasis in melanoma, breast cancer, and colon cancer models. This study pioneers a versatile nanoplatform that not only counteracts tumour immune evasion but also establishes durable anti-tumour immunity, offering a transformative approach to tumour immunotherapy.