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Cancer still represents a leading threat to human health worldwide. The effective usage of anti-cancer drugs can reduce patients’ clinical symptoms and extend the life span. Current anti-cancer strategies include chemotherapy, traditional Chinese medicine, biopharmaceuticals, and the latest targeted therapy. However, due to the complexity and heterogeneity of tumors, serious side effects may result from the direct use of anti-cancer drugs. Besides, the current therapeutic strategies failed to effectively alleviate metastasized tumors. Recently, an ultrasound-mediated nano-drug delivery system has become an increasingly important treatment strategy. Due to its ability to enhance efficacy and reduce toxic side effects, it has become a research hotspot in the field of biomedicine. In this review, we introduced the latest research progress of the ultrasound-responsive nano-drug delivery systems and the possible mechanisms of ultrasound acting on the carrier to change the structure or conformation as well as to realize the controlled release. In addition, the progress in ultrasound responsive nano-drug delivery systems will also be briefly summarized.