Sonosensitizers that can increase the concentration of reactive oxygen species (ROS) within a tumor microenvironment is a high priority for sonodynamic therapy (SDT). In this study, a functionalized, smart nanosonosensitizer based on Au-RuO2 nanoparticles (NPs) and selenium nanoparticles (Se NPs) that were electrostatically self-assembled onto the surface of Listeria innocua (LI) was used to create Bac@ARS. Au NPs provided the core in which RuO2 was deposited to form Au-RuO2 NPs. Additionally, the underlying properties of the Au NPs and Se NPs were used to optimize the sonosensitivity performance. Compared with pristine RuO2 NPs, Bac@ARS exhibits highly efficient ROS-producing activity. Furthermore, Bac@ARS remodeled the hypoxic tumor microenvironment, enabling overproduction of ROS. Importantly, Bac@ARS exploits the natural tropism of LI to selectively accumulate in tumors, which improved the treatment precision at hypoxic tumor sites after sonodynamic activation. However, the activity of LI was greatly reduced after ultrasound (US) irradiation, ensuring the biosafety of Bac@ARS. Bac@ARS was also used to monitor tumors, in real time, using photoacoustic imaging of the gold-based nanoparticles. Therefore, Bac@ARS is a promising microbial sonosensitizer providing a new platform for the optimization of sonosensitizers for tumor treatment. STATEMENT OF SIGNIFICANCE: A bio-nano-sonosensitizer was designed using a Au nanoparticle (NP) core modified with RuO2 NPs. The Au-RuO2 NPs together with Se-NPs are attached via electrostatic adsorption to a live bacterium Listeria innocua (LI), creating Bac@ARS. The role of the NPs was to optimize the sonosensitivity performance at the target tumor site. Bac@ARS reshaped the tumor microenvironment and overcame tumor hypoxia leading to ROS overproduction. This activated a potent ICD-mediated cellular immunity and anti-tumor activity. Importantly, Bac@ARS exploited the natural tropism of LI to selectively accumulate in tumors, resulting in more precise delivery of the therapeutic effect while exhibiting reduced effects on healthy tissues.

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