We develop pH-responsive GOD@CaCO3-Fe3O4 particles as catalytic nanomedicine for chemodynamic therapy through ultrasound-assisted Fenton reaction. By loading glucose oxidase (GOD) in the interior of the particles, GOD can be well protected and effectively delivered to catalyze glucose in cancer cells. A considerable amount of H2O2 is then generated for Fenton reaction by reacting with Fe3O4 nanoparticles. The introduction of ultrasound irradiation can significantly improve Fenton reaction efficiency in tumors owing to ultrasonic cavitation. Highly toxic hydroxyl radicals are then generated in abundance to kill cancer cells. Good cancer therapeutic effect was realized both in vitro and in vivo via this ultrasound-chemodynamic strategy based on the designed particles, providing a novel strategy for efficient cancer therapy.