Focused Ultrasound-Triggered Burst Release and Enrichment of Engineered Bacteria for Tumor Therapy

Ultrasound has been widely used in bacteria-based tumor therapy for targeted drug delivery due to its noninvasive ability to control bacteria. However, current approaches achieve only gradual release of therapeutic agents and rely on limited natural homing ability, resulting in poor treatment efficacy. Here, we demonstrate that focused ultrasound (FUS) can simultaneously induce burst release within tumors and local enrichment of therapeutics, enhancing precise and controllable spatiotemporal drug delivery efficiency within tumor microenvironments in living-therapeutic biomaterial system. We achieved FUS-triggered bacterial burst release by coexpressing gas vesicles (GVs), protein nanostructures that induce cavitation, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which increases antitumor efficacy. Furthermore, we show that FUS enhances enrichment of therapeutics at the tumor site by manipulating bacteria toward tumor vessel walls and increasing tumor permeability via sonopermeation. In a mouse model, we demonstrated clinical potential by achieving a 40% reduction in tumor volume using probiotic Escherichia coli Nissle (EcN) 1917 with a short 2-min FUS exposure and no exogenous agents. This work shows that physical ultrasound control provides an intuitive, highly efficient, and easily applicable biohybrid approach to bacteria-based tumor therapy, offering a simple and widely accessible strategy that can be broadly adapted to diverse living biomaterial systems.