CAREER: Nanoparticle mRNA and DNA Immunoengineering of Macrophages for Solid Tumor Targeting

The success of messenger RNA (mRNA) COVID-19 lipid nanoparticle (LNP) vaccines has opened new opportunities to engineer the immune system using mRNA LNP technology. An exciting target is engineering the immune system to treat solid cancer tumors which are difficult to treat with cellular immunotherapies. The goal of this CAREER project is to develop an LNP technology to engineer immune cells that can enter and kill solid tumors. This research goal is integrated with educational objectives to engage women, underrepresented, and first-generation STEM students in immunoengineering. The educational objectives of the project are to create immunoengineering modules for the NSF-funded International Summer School in Greece and the University of Pennsylvania Bioengineering course curriculum, develop K-12 immunoengineering demos with the Franklin Institute Science Museum of Philadelphia, and engage high school and undergraduate STEM students through research internships. The specific goal of this project is to exploit a nanotechnology platform to engineer macrophages using mRNA and plasmid DNA (pDNA) as a new means to generate an immune response against solid tumors. Cellular immunotherapies, such as chimeric antigen receptor (CAR) T cells, have been successful at treating blood cancers, but have had limited success in infiltrating solid tumors. Macrophages are actively recruited and readily infiltrate solid tumors. Therefore, there is immense potential for engineering CAR macrophages to stimulate the immune system to treat solid tumors. A new LNP platform will be employed that safely and efficiently delivers mRNA and pDNA into macrophages, as a new means to engineer CAR macrophages and characterize their interactions with solid tumor cells. This project aims to determine how LNP physicochemical properties influence mRNA and pDNA delivery to macrophages, to engineer and characterize CAR macrophages using LNPs, to assess their ability to target and kill solid tumor cells, and to quantify the ability of mRNA and pDNA CAR macrophages to infiltrate solid tumors and elicit an antitumor response in mice. The proposed studies will have a transformative impact on the development of immunotherapies to treat solid tumors, and the nanotechnology developed will enable macrophage immunomodulation for a range of applications, including infectious diseases, implants, autoimmune disorders, and mRNA COVID-19 vaccines. 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.