Photo-driven bacterial motor for tumor-targeted deep penetration and destruction while reducing hepatotoxicity

Live bacteria-based therapeutics show immense promise in cancer treatment due to their combined tumor-killing and immune-modulating functions. However, their clinical application is limited by their vulnerability to macrophage clearance, their struggle to penetrate deeply into tumors due to their micron-scale size, and their high off-target liver toxicity. In this study, we present the concept of "targeted photothermal microbial motor". This motor is created by loading photothermal nanoparticles onto the clinical attenuated Salmonella typhimurium VNP20009 (VNP) and encapsulating them within a macrophage membrane (IP@VNP@M). The encapsulation within the M1 macrophage membrane provides the motor with tumor-targeting enrichment capacity. Notably, this tumor-enriched bacterial motor can stimulate accelerated bacterial movement (a 4.0-fold increase in speed) under mild photothermal excitation by near-infrared (NIR) light. This acceleration, combined with the bacteria's hypoxia-targeting ability, enables deep tumor penetration and high uptake. The photothermal bacterial motor utilizes the synergy of photothermal effects and bacteria to polarize M2 phenotypic tumor-associated macrophages into the M1 phenotype. This results in efficient tumor killing and triggers a robust anti-tumor immune response, significantly extending the survival of tumor-bearing mice. Importantly, this precise tumor-targeting capability of the bacterial motor allows them to avoid the hepatotoxicity typically induced by VNP. Therefore, the bacterial motor presents a promising alternative for bacteria-based tumor therapy, offering enhanced efficacy and reduced toxicity.