Programmable Bacteria‐Based Biohybrids as Living Biotherapeutics for Enhanced Cancer Sonodynamic‐Immunotherapy

Abstract Synthetic biology is propelling medicine into a new era through its capacity to genetically program living cells. One of the particular interests is engineering bacteria as a live and targeted therapeutic delivery system. Herein, the bacterial biohybrid (E. coli‐pE@PCN) is developed by genetically engineering Escherichia coli BL21 to overexpress catalase (E. coli‐pE) and electrostatically adsorbing nano‐sonosensitizers (PCN NPs) for enhanced and targeted sonodynamic therapy (SDT). Leveraging the ability to colonize and penetrate deep in tumors, engineered bacteria can not only sustainably express catalase to relieve tumor hypoxia, but also facilitate the enriched and expanded distribution of the carried sonosensitizer at the tumor site, so as to trigger effective SDT. More interestingly, it is found that E. coli‐pE@PCN‐based SDT can successfully inhibit the growth of subcutaneous and orthotopic colorectal tumors by inducing potent antitumor immune responses due to the released tumor‐associated antigens and native immunogenicity of bacterial pathogen‐associated molecular patterns. Furthermore, E. coli‐pE@PCN‐based SDT can not only prime a strong immune memory response to prevent tumor recurrence but also elicit a potent abscopal effect to inhibit tumor metastasis. Therefore, the programmable bacteria‐based biohybrids developed here pave an avenue to prepare next‐generation sonodynamic‐immunotherapeutics to eliminate cancer and prevent its relapse and metastasis.