Engineered Akkermansia muciniphila vesicles for targeted pyroptosis and trained immunity to enhance immunotherapy in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) features a tumor immunosuppressive microenvironment (TIME) and limited response to immune checkpoint inhibitors (ICIs). To address this, we develop ultrasound-responsive nanoparticles by encapsulating PD-L1-targeting small interfering RNA (siRNA) and sonodynamic metal-organic frameworks (MOFs) into bacterial membrane vesicles (BMVs) derived from Akkermansia muciniphila. The siRNA-MOF@BMV (SMB) demonstrates HCC-specific accumulation via N-acetylgalactosamine (GalNAc) and induces pyroptosis through NLRP3/Caspase-1/GSDMD pathway activation under ultrasound, releasing tumor antigens. Simultaneously, SMB further induces trained immunity in tumor-associated macrophages (TAMs), promoting CXCL9(+) phenotypes that enhance antigen presentation and chemotaxis capacity. This increases cytotoxic CD8(+) T cell infiltration and reduces exhausted T cells, reshaping the TIME. Furthermore, SMB exhibits superior tumor suppression compared to clinical ICIs through systematic evaluations in orthotopic HCC mouse models, primary HCC models, patient-derived xenograft (PDX), and organoid models. SMB presents a multifunctional immunotherapeutic strategy integrating targeted pyroptosis induction, innate immune training, and ICI delivery, representing a potent immunotherapeutic agent for HCC.