Multifactorial regulation of ultrasound-induced cavitation by engineered silica nanoparticles

• Size-dependent nanoparticle-enhanced cavitation peaks at ∼ 100 nm. • Hollow mesoporous SiO 2 NPs exhibit the strongest cavitation enhancement effect. • Hydrophobic surface modification significantly reduces the cavitation threshold. • A unified concave-convex curvature theory elucidates the threshold lowering mechanism. • Engineered NPs reduce cavitation threshold to within FDA-safe intensity levels. Acoustic cavitation, characterized by the nucleation, growth, and collapse of cavitation bubbles under ultrasound irradiation, is a fundamental mechanism for therapeutic ultrasound, including high intensity focused ultrasound therapy and sonodynamic therapy (SDT). In this study, a hierarchical acoustic signal analysis was carried out to systematically evaluate how engineered silica nanoparticles (SiO 2 NPs) regulate cavitation onset, bubble growth, and oscillation stability. Specifically, cavitation thresholds were determined using the third harmonic signal, and calibrated to acoustic intensity (I SPTA ) to assess clinical safety. Our results demonstrate that nanoparticles facilitate bubble nucleation in a size-dependent manner, with maximal enhancement observed at ∼ 100 nm under 840 kHz ultrasound sonication. Structurally, hollow mesoporous silica nanoparticles (HMSNs) induced the most intense cavitation with the lowest threshold of 0.56 W/cm 2 , significantly below the FDA safety limit (3 W/cm 2 ). Furthermore, we propose a unified concave-convex curvature theory to elucidate these phenomena: hydrophobic modifications and hollow architectures create effective concave interfaces that stabilize gas nuclei, drastically lowering the nucleation barrier compared to convex hydrophilic spheres. These findings provide quantitative mechanistic insights into nanoparticle-mediated cavitation and establish key design principles for ultrasound-responsive nanoplatforms that enable effective therapy within clinically safe energy levels.