Systemically delivered Bacteroides thetaiotaomicron-derived bacterial extracellular vesicles inhibit primary and metastatic melanoma growth

The gut microbiome can contribute to anti-tumour immunity and cancer therapy responses, but translating live microbe-based interventions remains challenging due to safety, controllability, and delivery constraints. Bacterial extracellular vesicles (BEVs) are an attractive cell-free alternative, as they package bacterial cargo into a nanoscale format capable of host-cell engagement, immunological activation, and systemic distribution. Here, we investigated the anti-tumour potential of BEVs derived from the human gut commensal Bacteroides thetaiotaomicron (Bt). We show that delivery route is a major determinant of efficacy. Intravenous, but not intraperitoneal, administration produced robust anti-tumour activity in a B16F10 melanoma mouse model. Intravenously delivered Bt BEVs suppressed primary tumour growth in a dose-dependent manner and reduced metastatic outgrowth in the lung. Bt BEVs did not directly impair tumour-cell viability in vitro, but they activated NF-{kappa}B and Toll-like receptor signalling in innate immune reporter systems and localised to tumour tissue following systemic administration. Together, these data support a model in which Bt BEVs act via host immune modulation rather than direct tumour cytotoxicity. These findings identify naturally produced commensal-derived Bt BEVs as a potential microbial therapeutic modality and as an alternative to the use of live bacterial administration in cancer therapy.