CAREER: Engineering Membrane-Wrapped Nanoparticles for Targeted RNA Delivery

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NON-TECHNICAL The goal of this CAREER award is to develop nanoparticles that mimic the structure of cancer cells to enable tumor-specific delivery of ribonucleic acid (RNA) molecules. RNA delivery to tumors is a long-standing problem whose solution has exceptional promise, as RNA can suppress the expression of target genes that facilitate tumor growth. This project will package RNA inside polymeric nanoparticles, which are then "cloaked" with membranes derived from cancer cells, in order to hide the nanoparticles from the immune system and enable specific recognition of tumor cells inside the body. This project will generate the nanoparticles, characterize their material properties, and evaluate their cell-specific and tumor-specific RNA delivery capabilities. For emerging technologies like this to be successfully implemented in the future, a new generation of scientists must be trained how to develop and analyze innovative bio-nanomaterials. Accordingly, this project's educational goal is to create a comprehensive program spanning the K-12, college, and graduate levels that will increase students' exposure to the field and increase the pipeline of students, particularly women and minorities, pursuing careers in bio-nanotechnology. These efforts include the development of a new college course module about membrane-wrapped nanoparticles, the creation of demonstrations about bio-nanomaterials for use in K-12 outreach, and the in-depth training of high school and undergraduate students in bio-nanomaterials via research internships. By integrating the proposed research with these programs and targeting a large and diverse audience, this project will enable the next generation of workers in the field to create innovative solutions to grand challenges at the interface of nanotechnology, biology, materials science, and medicine.TECHNICAL This project will develop cancer cell membrane-wrapped nanoparticles (CCNPs) for targeted RNA delivery to tumors. The use of membrane cloaks to disguise nanoparticles from the immune system and enable tumor-specific delivery is at the forefront of modern cellular engineering, nanotechnology, and materials science, yet the features of these systems that are essential for their application in RNA interference remain unknown. While prior work has shown that covering synthetic nanoparticles with membrane coatings improves systemic delivery of hydrophobic drugs, the ability to provide targeted delivery of hydrophilic RNA cargos, as this project aims to do, has not yet been realized. This project will develop CCNPs for RNA delivery through three aims, which are to: (1) Synthesize CCNPs carrying RNA cargo and characterize their material properties and payload release; (2) Determine how the size and membrane composition of CCNPs influence their ability to engage cell receptors to mediate uptake and RNA payload delivery, and; (3) Demonstrate the homotypic targeting of CCNPs carrying RNA cargo both in vitro and in vivo. Together, these aims will advance fundamental knowledge of CCNP technology and produce a new platform that may improve the study and treatment of cancer. This project will also integrate this research into educational activities in order to inspire and prepare students for careers in STEM and bio-nanotechnology. The educational aims are to: (1) Create a new module about "membrane-wrapped nanoparticles for cargo delivery" for the Engineering Biomedical Nanostructures (EBN) course in the engineering curriculum; (2) Work with students in the EBN course to develop bio-nanomaterials demos for use in K-12 outreach facilitated by the University of Delaware Lending Library, and; (3) Engage high school and undergraduate students from groups underrepresented in STEM in bio-nanomaterials research via internships. These educational efforts will be evaluated annually to confirm their success in increasing the pipeline of students pursuing higher education and careers in bio-nanotechnology and other STEM disciplines.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.