Non-pathogenic Trojan horse Nissle1917 triggers mitophagy through PINK1/Parkin pathway to discourage colon cancer

Bacteria-mediated antitumor therapy has gained widespread attention for its innate tumor-targeting capability and excellent immune activation properties. Nevertheless, the clinical approval of bacterial therapies remains elusive primarily due to the formidable challenge of balancing safety with enhancing <i>in vivo</i> efficacy. In this study, leveraging the probiotic <i>Escherichia coli Nissle1917</i> (<i>EcN</i>) emerges as a promising approach for colon cancer therapy, offering a high level of safety attributed to its lack of virulence factors and its tumor-targeting potential owing to its obligate anaerobic nature. Specifically, we delineate the erythrocyte (RBC) membrane-camouflaged <i>EcN</i>, termed as Trojan horse <i>EcN</i>@RBC, which triggers apoptosis in tumor cells by mitigating mitochondrial membrane potential (MMP) and subsequently activating the PINK1/Parkin pathway associated with mitophagy. Concurrently, the decline in MMP induced by mitophagy disrupts the mitochondrial permeability transition pore (MPTP), leading to the release of Cytochrome C and subsequent apoptosis induction. Moreover, synergistic effects were observed through the combination of the autophagy activator rapamycin, bolstering the antitumor efficacy <i>in vivo</i>. These findings offer novel insights into probiotic-mediated antitumor mechanisms and underscore the therapeutic potential of <i>EcN</i>@RBC for colon cancer patients.