Breast cancer brain metastasis marks the most advanced stage of the disease with the median survival period of only 4-16 months. A major hurdle in developing therapeutic strategies to tackle breast cancer brain metastasis is our limited understanding of mechanisms involved in metastatic progression of breast cancer to the brain. This is, in part, due to lack of biomimetic in vitro models to study the interactions between metastatic breast cancer cells and the brain microenvironment. In addition, challenges associated with ineffectiveness of current diagnostic as well as therapeutic techniques in crossing the blood-brain barrier, and specifically labeling and targeting cancer cells pose further difficulties in treating metastatic brain malignancies. To address this issue, this dissertation focuses on engineering an in vitro hyaluronic acid (HA) hydrogel-based platform to investigate the microenvironmental regulation of breast cancer brain metastasis. HA hydrogel was chosen as it recapitulates key bio-physical and bio-chemical aspects of the native brain microenvironment. Specifically, this in vitro HA hydrogel-based platform was utilized to elucidate the mechanobiology underlying breast cancer brain metastasis. Further, the HA hydrogel-based platform was also adapted to model dormancy associated with brain metastatic breast cancer cells. Taken together, the in vitro biomimetic HA hydrogel-based platform for studying microenvironmental regulation of breast cancer brain metastasis, as presented in this dissertation, is a promising first step towards development of robust biomimetic strategies for studying breast cancer brain metastasis in a controlled setting. Finally, this dissertation also focuses on investigating the potential of ultrasmall iron oxide nanoparticles (< 4 nm) for labeling primary and metastatic brain cancer cells in vitro; to be utilized as a platform for tumor-targeted drug delivery and in imaging and early detection. Ultimately, such engineering approaches could provide mechanistic insight into the progression of breast cancer brain metastasis and enable the development of targeted therapeutics for the metastatic disease.