Advances in ultrasound-activated nano-sonosensitizers for cancer treatment: a systematic review and meta-analysis

Ultrasound (US)-activated nanotherapies represent a transformative frontier in oncology, leveraging the noninvasive deep penetration of acoustic energy for targeted tumor destruction. However, this field lacks a quantitative synthesis to guide the rational design of sono-sensitizing nanoparticles (NPs) and the optimization of therapeutic protocols. To address this issue, we performed a systematic review and meta-analysis of 144 recent research reports, establishing an evidence-based design hierarchy for nano-sonosensitizers. A meta-analysis of 86 in vitro studies revealed a profound synergistic reduction in cell viability when NPs were activated by US (pooled standard mean difference, SMD = -13.16, 95% CI [-14.67, -11.64], p < 0.001). NP size was the most influential design factor. Particles smaller than 50 nm showing the greatest effect in vitro (SMD = -13.32) and strongest tumor reduction in vivo (SMD = 5), a finding consistent with optimal exploitation of the enhanced permeability and retention (EPR) effect for tumor accumulation. Specific roles of materials were identified: polymeric NPs excelled in drug delivery (SMD = -19.36 versus US alone), while inorganic NPs served as direct sonocatalysts. This work provides a definitive quantitative framework to advance US-activated nanotherapy from exploratory discovery to clinical precision. To realize this potential, we recommend the adoption of standardized acoustic dosimetry and material characterization and inclusion of safety studies (ISO 10993. We hope that this review will accelerate the development of fundamental studies and therapeutic US applications for sonosensitizing NPs.