Focused ultraousnd (FUS) with the presence of microbubbles (MBs) has been demonstrated its capability of temporally and locally open the blood-brain barrier (BBB) that can be utilized to enhance chemotherapeutic drug delivery into the brain parenchyma for glioma treatment. However, the current administered chemotherapeutic agents that provide tumor-killing effect also induce systemic toxicity that significantly limits the dosage. Our previous results have already demonstrated the success of concurrently applying drug (BCNU)-loaded MBs with FUS exposures to open the BBB, which provided benefits in local drug delivery and reduced systemic toxicity. To further enhance the drug targeting and releasing capability of the drug-loaded MBs, we demonstrated here a novel VEGF-targeting, drug-loaded microbubble design for the use of FUS-BBB opening and brain drug delivery. This study may provide useful implications toward future MB design which aims to perform the targeted brain tumor therapy or extend the application of microbubbles on theragnostic purpose.