The development of ultrasound-responsive microcapsule structures has resulted in several spatiotemporally controlled drug delivery systems for macromolecular cargoes, including proteins, nucleic acids, and even cells for biomedical applications. However, utilizing microcapsules to transport small molecular cargoes remains a challenge, because the leakage of drugs before ultrasound irradiation might cause side effects such as the undesired toxicity and the decrease of effective drug concentration at the target site. Herein, we present a novel strategy to tackle these shortcomings by employing nanodrugs which refers to nanoparticles coated with small molecule drugs. We showed that the drug leakage was prevented when encapsulating the nanodrug in microcapsules. Moreover, the fabricated drug delivery system was responsive not only to unfocused high-intensity ultrasound but also to the clinically relevant high-intensity focused ultrasound. Finally, as a proof of concept, we showed that the antibacterial activity of the nanodrug@Microcapsules could be activated by applying ultrasound in situ. These results may provide new insights into the development of ultrasound triggered small molecule drug delivery assisted by metallic nanoparticles.