Dual metabolic modification of tumor-targeted bacteria for synergistic chemo-photodynamic therapy and immunotherapy

Conventional anti-tumor methods face challenges such as limited targetability and severe side effects, even when using carrier-assisted delivery of corresponding agents. Additionally, relying on a single modality often leads to an inadequate treatment response. Leveraging the facultative bacteria's migration tendency to hypoxic tumor tissue and the effectiveness of physicochemical approaches in bacterial engineering, non-pathogenic Escherichia coli MG1655 was metabolically modified for tumor-targeted and synergistic therapy. By taking advantage of the essential D-alanine (D-Ala) component in bacterial peptidoglycan, chemotherapeutic D-Ala-OXA and photosensitizing D-Ala-PPa were firstly prepared and simultaneously labeled on MG1655, creating the multimodal platform (O/P@MG1655). When exposed to red light irradiation, O/P@MG1655 effectively eliminated tumor cells through chemo-photodynamic therapy and induced immunogenic cell death to trigger immunotherapy. Notably, significant inhibition of tumor growth and excellent biosafety were observed in a subcutaneous CT26 mouse tumor model. This dual metabolic modification strategy represents a remarkable advancement in the development of functionalized targeted bacteria for precise tumor treatment.