The blood-brain barrier stands between the central nervous system and peripheral blood circulation, preventing entry of potential toxins into the brain but also inhibiting the successful delivery of drugs. This prevents the effective imaging, diagnosis and treatment of deadly brain-related diseases such as Alzheimer?s, Parkinson?s disease and brain cancer. As such, there is a tremendous demand for delivery systems which can solve these problems and effectively treat brain disease. Natural materials such as ferritin proteins have been shown to self-assemble into nanocages and cross the blood-brain barrier. However, a complete understanding of how these nanocages move across the barrier into the brain as well as their structure-function relationships has remained elusive. This research project will combine bioengineering and chemical approaches to understand how these nanostructures interact with the blood-brain barrier and to rationally design nanocages which have the capability to cross blood-brain barriers and to achieve cellular delivery. The project will provide a robust nanoparticle tool to study nanomaterial-biological barrier interactions and will advance the science for the development of next generation brain drug delivery and imaging platforms and techniques. This project brings together several key technology areas, including nanomaterials, chemical engineering, cell biology and biomedical engineering, providing interdisciplinary training for a diverse group of graduate and undergraduate students as well as exposing students from local high schools to cutting-edge research.
The central goal of the research project is to achieve a comprehensive understanding of protein based nanocage/blood-brain barrier interactions using ferritin as a model protein and subsequently to use this knowledge to develop a novel family of protein nanocages as brain targeted, modular delivery platforms with additional functionalities available on demand. The central hypothesis is that with rational design, the engineered ferritin protein can maintain its ability to assemble into nanocages, cross the biological interface of the blood-brain barrier, and also be conferred with new abilities for targeted delivery, loading of therapeutics and/or imaging agents. The research project seeks to: 1) design and genetically introduce targeting domains to ferritin proteins, assemble the ferritin proteins into ferritin nanocages, 2) investigate the nanocages? blood-brain barrier traversing and cellular targeting capabilities using cellular models; and 3) study the nanocage structure-biological function relationship. The scope of the project includes probing protein nanocage interactions with biological systems to elucidate the genetically-directed nanoscale modular design and providing theragnostic data on the potential treatment of many brain diseases. The ultimate goal of the project is to develop a genetically designed and chemically engineered nanoscale delivery system which can deliver therapeutic and diagnostic agents across the impenetrable blood-brain barrier. Overall, the experiments will probe nanoscale transport mechanisms and explore the interactions between engineered nanocages and biological systems, therefore laying the foundation for design and production of a new paradigm of protein-based theranostic systems. The educational components of this proposal will involve youth from underrepresented groups with a goal to attract, inspire and train the next generation of STEM professionals.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
