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

Abstract

AbstractCombination 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.