With an increasing number of women serving in the military, there is a significant need to effectively manage our active duty and Veteran women who develop breast cancer. In the United States alone, ~276,000 women will be diagnosed with breast cancer, of whom ~42,000 are predicted to die from this disease this year. Patients diagnosed with triple negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)- positive breast cancer have an increased likelihood of distant recurrence in the brain compared to other breast cancer subtypes – exceeding 35% of metastatic breast cancer patients. Brain metastases (BMs) confer dismal prognosis, as existing treatments have very limited efficacy; indeed, median survival for TNBC patients after detection of metastatic disease is ~5 months. Multiple unique barriers limit effective drug delivery to breast cancer BMs. These barriers include (i) the blood-brain barrier (BBB) within the normal brain parenchyma and the blood- tumor barrier (BTB) within metastatic lesions; (ii) elevated tumor interstitial pressure and the dense electrostatically charged brain extracellular spaces (ECS) which together limit convective and diffusive drug penetration; (iii) the activity of multidrug resistance (MDR) pumps expressed by both brain capillary endothelial cells and tumor cells, which reduce drug levels within tumor cells; and (iv) the brain glialymphatic system (GLS), which acts as an efficient drug clearance system. Thus, new therapeutic delivery strategies designed to mitigate and surmount these barriers will likely offer new promise towards effectively treating BMs. Accordingly, we propose to couple an emerging therapeutic delivery technology, decreased nonspecific adhesivity, receptor-targeted nanoparticles (DART NPs) with MRI-guided focused ultrasound (MRgFUS) for treatment of breast cancer BMs (BCBMs). DART NPs will be engineered to target Fn14, a member of the TNF receptor superfamily that is highly expressed in primary breast cancer and breast cancer BMs; but minimally in normal breast, brain, or other organs. Research findings from our team related to the development and application of DART NPs and MRgFUS-enhanced drug delivery that motivate the proposed studies include: (1) DART NPs rapidly penetrate in brain and breast tumor tissues ex vivo, selectively targeting Fn14-positive tumor cells both in vitro and in vivo, and significantly enhancing drug retention within intracranial tumors in vivo. (2) MRgFUS-induced BBB disruption (BBBD) can safely increase DART nanoparticle delivery into the normal brain parenchyma. (3) Fn14-targeted DART NPs containing the chemotherapeutic paclitaxel (PTX-DART NPs) are more effective than free PTX in killing cancer cells that overexpress the MDR1 efflux pump. (4) PTX-DART NPs more effectively reduce tumor growth and improve animal survival in mammary fat pad and intracranial TNBC xenograft models compared to Abraxane, an FDA-approved nanotherapeutic currently used...