Engineered bacteria and bacteria-derived nanomaterials for cancer therapy: Mechanisms, designs and advances

Bacteria have emerged as powerful and versatile platforms for cancer therapy, leveraging their inherent tumor-targeting capabilities, adaptability to engineering, and ability to interact dynamically with the tumor microenvironment (TME). This review systematically introduces the multimodal mechanisms of action underlying bacteria-based cancer therapeutics, from direct tumor lysis to bacterial tropism and immune modulation in the TME. We summarize engineering strategies for bacteria-based cancer therapy through two principal approaches: biological engineering (genetic reprogramming and biofilm encapsulation) and physicochemical modification (chemical conjugation, physical interaction, and biomineralization coating). This discussion highlights the key applications of live bacteria, including facultative anaerobes (e.g., <i>Salmonella typhimurium</i> (<i>S. typhimurium</i>) and <i>Escherichia coli</i> (<i>E. coli</i>), obligate anaerobes (e.g., <i>Clostridium</i>), and probiotics (e.g., <i>Bifidobacterium</i>), for precision oncotherapy. In addition to whole-cell therapies, we introduce bacterial derivatives such as outer membrane vesicles (OMVs) and membrane-coated nanoparticles as complementary approaches. Finally, we discuss key translational challenges in bacteria-based cancer therapies, including strain optimization, immune-related adverse effects, and manufacturing scalability. This review consolidates current advances in bacterial cancer therapy, offering a design framework to optimize microbial therapeutics. By bridging engineering principles with clinical needs, it provides actionable insights for developing safer, more effective living medicines against cancers.