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. • SMB nanoparticles integrate pyroptosis induction and immune checkpoint silencing • SMB nanoparticles trigger ultrasound-responsive pyroptosis and remodel TIME • SMB nanoparticles reprogram TAMs toward CXCL9 + macrophages and enhance CTLs • SMB nanoparticles show potent antitumor efficacy in preclinical HCC models Wang et al. engineer A. muciniphila -derived vesicles to co-deliver PD-L1 siRNA and sonodynamic MOF. The nanoparticles trigger pyroptosis, induce trained immunity in tumor-associated macrophages, enhance cytotoxic T cell infiltration, and achieve potent antitumor efficacy in HCC models.