It is estimated that around 15% to 40% of cancers spread to the central nervous system (CNS). The treatment of cancers with brain metastases, however, has been limited by the inefficient deliver of therapeutics to the CNS. We propose herein a novel strategy, which enables effective delivery of monoclonal antibodies (mAbs), a class of highly specific and potent protein therapeutics, to the CNS, for the treatment of cancers with brain metastases. This strategy is based on a nano-encapsulating technology, where mAbs molecules are encapsulated within nanocapsules of which the surface contains abundant choline and acetylcholine analogues. Such nanocapsules can be effectively transported across the BBB and deliver the mAbs to the CNS upon systemic administration. Furthermore, the nanocapsules can be targeted by conjugation with ligands which recognize cell surface markers on tumor cells. We recently published effective delivery into the CNS of rituximab (anti-CD20) mAbs through intravenous route using the nanocapsule technology. The nanocapsules were targeted to CXCR5 on the surface of the tumor cells via conjugation with CXCL13. This therapeutic approach significantly reduced the tumor burden in the brains of mice xenografted with B-cell lymphomas in comparison with direct native mAbs. In this proposal, we will further improve the therapeutic efficacy by optimizing the design of the rituximab nanocapsules based on understanding of the mechanisms of BBB passage and tumor clearance. Success of this project could potentially enable effective delivery of many other therapeutic mAbs to the CNS, opening a new avenue for treatments of cancers with CNS metastases.