Low-energy ultrasound (LEUS) shows distinct potential as a safe therapeutic strategy for cancer treatment. Herein, mesoporous silica nanoparticles with closed-end cavities as sensitive nanoagents are prepared for effective cancer cell killing, when synergistically combined with mild LEUS (1 MHz, a parts per thousand currency sign1.0 W cm(-2)). The closed-end cavities can entrap gas bubbles, and provide a large number of cavitation nucleation sites, which could lead to drastically amplify ultrasonic cavitation effect by responding to the mild LEUS (1 MHz, a parts per thousand currency sign1.0 W cm(-2)). Significant killing effect against cancer cells is observed, when cells are treated by synergetic combination of mild LEUS and the nanoagents with closed-end cavities, showing distinct dose dependency on the nanoagents and irradiation intensity. Nevertheless, the killing effect is disappeared when the closed-end cavities are destructed. Moreover, no obvious cytotoxicity is observed when either the nanoagents or the LEUS is applied alone. The research may open up application opportunities of mild low-energy ultrasound for cancer therapy.