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

Abstract 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 (O 2 ) for reactive oxygen species (ROS) generation and the necessity to avoid O 2 for the activation of HAPs. In this study, this challenge is addressed by developing BiOCl‐Au‐Ag 2 S Z‐scheme heterostructure nanoparticles loaded with tirapazamine (TPZ) to achieve O 2 ‐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 O 2 . 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 O 2 requirement in SDT and introduces a novel strategy for HAP activation and synergistic therapy between ROS and HAPs‐based therapy.