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Reversal of drug resistance and targeted therapy are the keys but remain challenging in resistant breast cancer treatment. Herein, low frequency ultrasound detonated “nano bombs” were rationally designed and used for treatment of resistant breast cancer. For the ‘nano bombs’, the ammunition (Doxorubicin, DOX) was loaded into the ammunition depot (hollow mesoporous TiO2, MTNs), and the safety device (dsDNA) was wrapped on the surface of MTNs to avoid the unexpected DOX release. We found the “US-detonated explosive” abilities of “nano bomb” MTNs (NBMTNs), including explosive generation of ROS, explosive release of DOX, US-triggered lysosome escape and mitochondrial targeting in the in vitro and in vivo studies. More importantly, the drug resistance of MCF-7/ADR cells could be reversed via the inhibition of mitochondrial energy supply approach caused by the “explosion” of NBMTNs. Furthermore, NBMTNs combined the superior chemotherapy efficacy of DOX and potent SDT efficacy in one single platform and significantly enhanced the anticancer efficacy. Our results demonstrate an approach for reversing resistance and specific targeting of tumors using ‘US-detonated nano bombs’.Through a combination of ultrasound-detonated drug release and synergistic treatment, the ‘nano bombs’ open a window for achieving maximal anticancer efficacy with minimal side effects in drug-resistant tumor-bearing mice.