An Integrated Engineered Bacterial Nanocomposite System for Targeted Prodrug Delivery and Enhanced Antitumor Efficacy

Abstract Even with the promising therapeutic potential of engineered bacteria that target tumors, effective cancer treatment will still need to involve combination strategies. Herein, a model strain of Escherichia coli (BL21) is aimed to engineer to internally produce copper sulfide nanoparticles (CuS), which are subsequently armed with disulfiram‐loaded gold nanorods, resulting in Au‐DSF@CuS‐BL21 for hypoxic‐targeted prodrug delivery and enhanced antitumor effects. The bacterial membrane in this system serves as a barrier between the prodrugs of CuS and DSF, preventing the premature formation and release of the highly toxic CuET complex during circulation, thus ensuring bacterial survival and minimizing drug leakage. The key findings revealed that bacterial activity of Au‐DSF@CuS‐BL21 is effectively sustained, exhibiting enhanced capabilities for tumor targeting and penetration. Upon activation by 808 nm near‐infrared laser irradiation, photothermal bacterial lysis is induced, resulting in the release of CuS and DSF. This process facilitate the formation of the highly toxic CuET complex, as well as augmented antitumor efficacy by stimulating the innate immune response. Collectively, these findings offer promising opportunities for enhancing the biosafety of modified bacteria, as well as for compartmentalized prodrug delivery and improved effectiveness of combination antitumor therapies.