Bioengineered Escherichia coli Nissle 1917 with hematoporphyrin monomethyl ether for targeted sonodynamic therapy and immune activation in ovarian cancer

Abstract

Ovarian cancer remains one of the most lethal gynecological malignancies worldwide. Sonodynamic therapy (SDT) offers a non-invasive treatment modality. However, the clinical efficacy of SDT is hampered by the insufficient tumor accumulation of sonosensitizers. Escherichia coli Nissle 1917 (EcN) stands out as a clinically approved strain with an excellent safety profile and tumor targeting ability. In this study, we developed a bioengineered probiotic platform utilizing EcN, surface-functionalized with hematoporphyrin monomethyl ether (HMME) and water-soluble chitosan, to enhance SDT and facilitate immune activation in ovarian cancer. The engineered probiotic HW@EcN, exhibited significant tumor-targeting ability, selectively accumulating in acidic tumor microenvironment (TME) and releasing HMME in a pH-responsive manner. Upon ultrasound (US) activation, HW@EcN generated reactive oxygen species (ROS), leading to tumor cell death and enhanced immune responses. In vivo studies using a C57BL/6 murine model demonstrated selective targeting of HW@EcN by tumor, and effective tumor growth inhibition, with significant immune activation indicated by increased CD4⁺ and CD8⁺ T cell and elevated IFN-γ levels. Histopathological analysis confirmed the biocompatibility of HW@EcN with minimal off-target toxicity. This bioengineered probiotic platform HW@EcN presents a clinically translatable approach for improving SDT efficacy and immune activation, paving the way for innovative cancer therapies.