The delivery of systemically administered gene-therapies to brain tumors is exceptionally difficult due to the blood-brain (BBB) and blood-tumor (BTB) barriers. Additionally, the adhesive and nanoporous tumor extracellular matrix hinders therapeutic dispersion. Here, we first developed the use of magnetic resonance (MR) image-guided focused ultrasound (FUS) and microbubbles (MBs) as a platform approach for transfecting brain tumors by targeting the delivery of systemically administered “brain-penetrating” nanoparticle (BPN) gene vectors across the BTB/BBB. Next, using an MRI-based transport analysis, we determined that, after FUS-mediated BTB/BBB opening, mean interstitial flow velocity magnitude doubled, with “per voxel” flow directions changing by an average of ~70⁰-80⁰. Finally, we observed that FUS-mediated BTB/BBB opening elicited a >100% increase in the dispersion of directly injected BPN through tumor tissue. We conclude that FUS-mediated BTB/BBB opening yields markedly augmented interstitial tumor flow that, in turn, plays a critical role in enhancing BPN transport through tumor tissue.