Development of Lipid Nanoparticles for B-cell Mediated Immunotherapies - Gene therapy has had an exciting last decade with many novel FDA approved therapies reaching the clinic. These treatments have not only been fruitful in cancer treatment, but also for genetic diseases and, more recently, in COVID-19 vaccines. Unlike macromolecules or small molecules, nucleic acids (DNA or RNA) require an efficient engineered delivery vehicle for effective treatment owing to either their high negative charge or high degradation rate which hinder cellular entry and systemic circulation, respectively. Although challenging to deliver, nucleic acids have a highly modular payload given that, with similar biophysical properties, they can transcribe or translate into a wide range of products, making the way for a truly modular platform for therapeutic delivery. Compared to systemic macromolecule administration, the delivered nucleic acid cargo can promote local and long-lasting production of a target therapeutic such as a cytokine for immunotherapy. Further, many promising gene modulation approaches exist beyond the delivery of a gene for transcription or translation such as RNA interference, gene silencing, antisense therapy, and gene editing. Consistent with the goals of nanotechnology for cancer treatment provided by the NCI, this project will focus on designing and characterizing the stability of lipid nanoparticles (LNPs) to induce an anti-tumor immune response. The target immune response will be mediated by B cell responses via CMTR2 depletion, an exciting new pathway to induce anti-tumor immune responses. Combination strategies using CMTR2 depletion with other immunomodulatory treatments will also be explored to further enhance the B- cell responses.
