Bacterial missile with ultrasound-triggered prodrug release for targeted pancreatic cancer therapy

Pancreatic cancer poses a severe clinical challenge owing to its deep-seated site, inefficient drug delivery, poor tumor penetration, and systemic toxicity of conventional chemotherapy. Herein, we fabricated an ultrasound-responsive “bacterial missile” via in situ atom transfer radical polymerization (ATRP) on attenuated Salmonella VNP20009. Thioketal-linked 5-fluorouracil (5-Fu) prodrugs were densely grafted onto bacteria to form a protective polymer shell, enabling high drug loading, reducing off-target toxicity, and shielding surface antigens to alleviate excessive immunogenicity. Manganese carbonate (MnCO 3 ) nanoparticles were further assembled onto the engineered bacteria to construct VNP@P5-Fu@Mn. Under ultrasound irradiation, reactive oxygen species cleave thioketal bonds for on-demand 5-Fu release, while released Mn 2+ activates the cGAS–STING pathway. The living bacterial chassis actively penetrates dense tumor stroma and targets deep lesions. In vitro and in vivo studies confirm that this system induces robust immunogenic cell death, promotes dendritic cell maturation, enhances CD8 + T-cell infiltration, and effectively inhibits orthotopic pancreatic tumor growth with minimal systemic toxicity. This work integrates bacterial targeting, ultrasound-controlled prodrug activation, and cGAS–STING-mediated immunotherapy, offering a programmable and translatable living therapeutic platform for precise treatment of deep-seated solid tumors. We developed an ultrasound-responsive “bacterial missile” by grafting chemotherapy prodrugs onto attenuated Salmonella via ATRP. This system leverages bacterial tumor targeting for deep accumulation and uses ultrasound for precise drug release at the tumor site, enhancing efficacy while minimizing off-target damage to normal tissues. This strategy offers a promising approach for precise deep-tumor therapy.