Oxygen-Independent Synchronized ROS Generation and Hypoxia Prodrug Activation with Z-Scheme Heterostructure Sonosensitizer

Combination therapy has emerged as a promising approach for effective tumor treatment. However, the combination of sonodynamic therapy (SDT) and hypoxia-activated prodrugs (HAPs) has not been explored due to the contradictory requirement of oxygen (O₂) for reactive oxygen species (ROS) generation and the necessity to avoid O₂ for the activation of HAPs. In this study, this challenge is addressed by developing BiOCl-Au-Ag₂S Z-scheme heterostructure nanoparticles loaded with tirapazamine (TPZ) to achieve O₂-independent therapy. These nanoparticles demonstrate efficient electron–hole separation under ultrasound irradiation while maintaining a high redox potential. The generated holes react with water to efficiently produce hydroxyl radicals, while the electrons autonomously activate TPZ, negating the need for O₂. In vitro and in vivo assessments validate the effective tumor elimination by these Z-scheme nanoparticles without disrupting the hypoxic environment. This innovative design overcomes the limitations associated with O₂ requirement in SDT and introduces a novel strategy for HAP activation and synergistic therapy between ROS and HAPs-based therapy.