Bacteria-Mediated Tumor Therapy Utilizing Photothermally-Controlled TNF-alpha Expression via Oral Administration

Oral drug administration is widely adopted for diverse drugs and is convenient to use due to the capability of reaching different parts of the body via the bloodstream. However, it is generally not feasible for biomacromolecular antitumor drugs such as protein and nucleic acids due to the limited absorption through gastrointestinal tract (GIT) and the poor tumor targeting. Here, we report a noninvasive thermally sensitive programmable therapetic system using bacteria E. coli MG1655 as an vehicle for tumor treatments via oral administration. Thermally sensitive programmable bacteria (TPB) are transformed with plasmids expressing therapeutic protein TNF-alpha and then decorated with biomineralized gold nanoparticles (AuNPs) to obtain TPB@Au. AuNPs and TNF-alpha plasmids efficaciously protected by TPB in the gut can be transported into internal microcirculation via transcytosis of microfold cells (M cells). After that, the bacteria-based antitumor vehicles accumulate at tumor sites due to the anaerobic bacterial feature of homing to tumor microenvironments. In vitro and in vivo experiments verify the successful delivery of AuNPs and TNF-alpha plasmids by TPB. Importantly, under remote activation the expression of TNF-alpha in tumor sites can be procisely controlled by the heat generated from photothermal AuNPs to exert therapeutic actions. The biological security evaluation demonstrates that this strategy would not disturb the balance of intestinal flora.