Augmenting sonodynamic therapy with single-atom nanoenzyme via tumor microenvironment-mediated reactive oxygen species generation

While remarkable strides have been made in personalized precision oncology, integrating diagnosis and therapy within a unitary theranostic platform remains a pivotal challenge. Sonodynamic therapy (SDT), which leverages ultrasound to activate sonosensitizers for generating tumoricidal reactive oxygen species (ROS), offers distinct advantages including non-invasiveness, spatiotemporal precision, and deep tissue penetration. Its capability to visualize tumors by converting acoustic signals into diagnostic images presents a further unique merit. However, SDT efficacy is constrained by suboptimal sonosensitizer efficiency, the hypoxic tumor microenvironment, and augmented antioxidant defenses. Single-atom nanozymes (SANs) emerge as a transformative strategy to overcome these hurdles. They catalytically decompose endogenous hydrogen peroxide to alleviate hypoxia, deplete glutathione to disarm antioxidant defenses, and harness piezoelectric synergies. The integration of SANs' atomic-level catalytic architecture with sonosensitizers' ultrasonic responsiveness facilitates tumor hypoxia mitigation and enables image-guided precision therapy. This review systematically elucidates the molecular design of SAN-based sonosensitizers, analyzes their catalytic mechanisms for enhancing SDT, and discusses associated challenges and future directions for clinical translation. It aims to lay a theoretical foundation for developing next-generation sonodynamic SANs that are intelligent, safe, and environmentally benign. [PubMed and Web of Science, from inception to June 2025].