PROJECT SUMMARY Therapeutic monoclonal antibodies (mAbs), such as rituximab, have produced significant improvement in the mortality rates of patients with non-Hodgkin lymphoma (NHL). However, fundamental issues with antibody therapy such as poor tissue penetration of antibodies, non-specific antibody delivery, escape from antibody recognition, and eliciting of an immune response against antibodies, remain unsolved. We have developed a nanodelivery platform for macromolecules whereby an individual “cargo” is encapsulated within a thin polymer shell, termed a “nanocapsule”. Our platform is highly adaptable, allowing us to customize various properties, including cell surface affinity, cargo immunogenicity, cargo release rates, in vivo circulation times, and biodistribution, by altering the surface chemistry of the nanocapsules. Our nanocapsules are inert, highly stable, and resistant to protein adsorption, which are properties necessary for increased blood circulation times and elimination of cargo immunogenicity. Importantly, our nanocapsules do not enter into cells due to their neutral surface charge, but can still efficiently enter the central nervous system (CNS) and reduce cancer burden in the brain and eyes of human Burkitt lymphoma xenograft mice; this could be because the retina is part of the CNS. These indicate that they are ideal carrier vehicles for extracellular delivery of therapeutic mAbs to locations such as the brain and eyes, where penetration of antibodies is extremely poor. The ultimate goal of the proposed studies is to establish a clinically relevant in vivo delivery platform for therapeutic mAb drugs, thus enabling efficient elimination of cancers, especially those that have metastasized into the CNS or eyes.