Pyroptosis‐Amplified Decoy Nanovesicles Orchestrate Pyroptotic Antigen Explosion and Endogenous Immune Revitalization for Potentiating Tumour Immunotherapy

Abstract

ABSTRACT 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.