Albofungin vesicle nanobombs trigger lysosomal disruption for self-enhanced pyroptosis and cGAS-STING pathway activation in glioblastoma immunotherapy.

Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy.