From sound waves to systemic cure: transformative nanotechnology-driven sonodynamic Strategies in liver cancer.

Abstract

Liver cancer is the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) accounting for nearly 75-85% of total cases. As per recent global cancer estimates, over 900,000 new cases and more than 800,000 deaths occur annually, reflecting its high incidence and poor survival outcome. Despite advancements in surgical, systemic, and immunotherapeutic approaches, treatment efficacy for advanced HCC remains limited due to tumour hypoxia, recurrence, drug resistance, and off-target toxicities. Sonodynamic therapy (SDT), a non-invasive, ultrasound-activated therapeutic modality, has emerged as a promising strategy owing to its deep tissue penetration, minimal invasiveness, and controllable ROS-mediated cytotoxicity. Nanotechnology-enabled SDT significantly enhances sonosensitizer stability, tumour-specific delivery, and multifunctional therapeutic effects. Recent innovations include the development of organic, inorganic, and hybrid nano-sonosensitizers, along with synergistic combinations such as gene therapy, immunotherapy, chemotherapy, ferroptosis, pyroptosis, cuproptosis, and disulfidptosis induction. Moreover, image-guided SDT using ultrasound, MRI, and fluorescence platforms allows precise localisation and real-time therapeutic monitoring. Despite these promising advancements, clinical translation faces challenges involving biosafety, biodegradability, targeting specificity, and lack of standardised SDT protocols. This review comprehensively highlights SDT mechanisms, nanoplatform classifications, recent therapeutic strategies, safety concerns, and future research directions to facilitate effective and translational SDT-based liver cancer therapy.