RNA-Lipid Nanoparticles 2.0: From gene silencing to genome editing
A growing body of work is highlighting genes and signaling pathways that are impaired in human disorders and that may be potential candidates for treatment. The development of nucleic acid-based tools to manipulate gene expression, such as siRNAs, mRNAs, and genome editing strategies, opens up opportunities for personalized medicine. Yet, although major progress has been made in the development of targeted RNA vectors, primarily using monoclonal antibodies (mAbs) for targeting, their clinical translation has not occurred. This is due in part to the massive development and production requirements and the high batch-to-batch variability of current technologies, which rely on chemical conjugation. Here we present a self-assembling modular platform that allows the construction of a theoretically unlimited repertoire of RNA-targeted transporters. The self-assembly of the platform is based on a membrane-anchored lipoprotein embedded in novel RNA-loaded single lipid nanoparticles that interact with the Fc domain of antibodies. We show that a simple change of 8 different mAbs redirects the specific uptake of siRNA by various leukocyte subsets in vivo. The therapeutic potential of the platform is demonstrated in a model of inflammatory bowel disease, targeting colonic macrophages to reduce inflammatory symptoms, and in a xenograft model of mantle cell lymphoma, targeting cancer cells to induce cell death and improve survival. In addition, I will discuss a novel approach to deliver modified mRNAs to specific cell types in vivo using this platform. I will also share some data on mRNA vaccines for COVID19 and finally, I will share new data showing highly effective genome editing in glioma and metastatic ovarian cancer. This modular delivery platform can serve as a milestone in making precision medicine feasible.