Advanced strategies in nanosonosensitizer engineering for superior sonodynamic therapeutics

Sonodynamic Therapy (SDT) is a promising non-invasive therapeutic strategy that leverages the excellent tissue penetration ability of ultrasound to activate sonosensitizers, which in turn generate cytotoxic reactive oxygen species (ROS) locally. This approach offers unique advantages for the precise treatment of deep-seated lesions, such as solid tumors. However, traditional sonosensitizers (including organic small molecules and inorganic nanomaterials) suffer from inherent limitations, such as poor water solubility, rapid in vivo metabolism, and low ROS quantum yield, which significantly restrict the efficacy of SDT and its clinical translation. The rise of nanoscience and technology has led to revolutionary breakthroughs in this field, with high-performance nanomaterials engineered to address these challenges. This review comprehensively surveys and delves into the cutting-edge strategies for optimizing the performance of nanosonosensitizers. These strategies are categorized into three main directions: (1) Optimization of organic sonosensitizers delivery systems: Improving water solubility, stability, and targeting capability of organic sonosensitizers using lipid nanoparticles, polymers, biomimetic carriers, and porous materials. (2) Material regulation of inorganic sonosensitizers: Enhancing their sonodynamic activity through strategies such as defect engineering, element doping, single-atom catalysts, phase engineering, and interface engineering ( e.g. , constructing core-shell, Janus, or other heterojunctions) to optimize their energy band structure. (3) Precision design of metal-organic frameworks (MOFs)-based sonosensitizers: Enhancing the synergistic effect of SDT by controlling building blocks, loading functional molecules, or constructing heterojunctions. The review discusses recent advancements of these strategies in detail, with a focus on the application and efficacy of advanced nanosonosensitizers in cancer treatment. Finally, the review outlooks the key challenges and opportunities for future development in this field, aiming to provide valuable insights to advance the clinical translation of SDT. • Research Progress and Optimization Strategies for Organic Sonosensitizers. • Research Progress and Optimization Strategies for Inorganic Sonosensitizers. • Research Progress and Optimization Strategies for Metal-Organic Framework-based Sonosensitizers. • Stimuli-Responsive Designs for Precise and Controlled Drug Release in Nanosonosensitizers. • Limitations and Future Directions for the Development of Nanosonosensitizers in Cancer Theranostics.