Unveiling the mechanistic principles and engineered exploitation of bacteria and derivatives in precision drug...

The core of precision medicine lies in the efficient and specific delivery of therapeutic agents to disease sites. Traditional synthetic nanocarriers face inherent limitations in navigating complex biological barriers and responding to dynamic disease microenvironments. This review systematically explores the engineering strategies and application potential of four cutting-edge bacterial-derived delivery systems. Live biotherapeutic products (LBPs) serve as "living factories", utilizing genetic circuits to sense the disease microenvironment and produce therapeutic molecules in situ. Bacterial secretion systems (T1SS-T7SS) are repurposed as precise "molecular syringes" to directly translocate effector proteins, nucleic acids, and other cargoes into target cell cytosol or specific compartments. Extracellular contractile injection systems (eCISs) function as autonomous, pre-assembled "nanosyringes" that utilize a spring-loaded mechanism for direct cytosolic injection, offering a non-viral, high-efficiency delivery platform. Bacterial extracellular vesicles (bEVs), as natural nanocarriers, are engineered for targeted drug delivery and immunomodulation. The article compares the delivery mechanisms, payload characteristics, engineering flexibility, and clinical translation challenges of these platforms. The future advancement of this field will rely on the deep integration of synthetic biology, nanotechnology, and immunology to develop intelligent therapeutic platforms that are simultaneously potent, safe, and controllable.