Engineered Akkermansia muciniphila Vesicles for Targeted Pyroptosis and Trained Immunity to Enhance Immunotherapy in Hepatocellular Carcinoma (PRJCA041597)
This study engineered ultrasound-responsive nanoparticles (SMB) by encapsulating PD-L1-targeting siRNA and sonodynamic metal-organic frameworks (MOF) within probiotic Akkermansia muciniphila-derived bacterial membrane vesicles (BMVs). SMB nanoparticles demonstrated HCC-specific accumulation via GalNAc-mediated hepatocyte targeting and induced pyroptosis through NLRP3/Caspase-1/GSDMD pathway activation under ultrasound, promoting tumor-associated antigen release. Simultaneously, SMB nanoparticles further induced a trained immunity signature in tumor-associated macrophages (TAMs), and reprogrammed them into CXCL9+ phenotypes. These macrophages exhibited enhanced antigen presentation and chemotaxis capacity, eliciting cytotoxic CD8+ T cell infiltration while reducing exhausted T cell populations, thereby reshaping the TIME in HCC. Furthermore, SMB nanoparticles exhibited superior tumor suppression compared to clinical ICIs through systematic evaluations in orthotopic HCC mouse models, oncogenic plasmid induced primary HCC models, patient-derived xenograft (PDX), and organoid models. These findings present a multifunctional immunotherapeutic strategy integrating targeted pyroptosis induction, innate immune training, and ICI delivery, suggesting that SMB nanoparticles may represent a potent immunotherapeutic agent for HCC treatment.