Resveratrol enhances mRNA and siRNA lipid nanoparticles transfection

mRNA and siRNA therapies encapsulated in lipid nanoparticles (LNPs) are the most advanced clinically accepted platform for RNA delivery. RNA-LNPs are utilized for a wide variety of applications, with three clinically approved RNA-LNPs including the recent mRNA-LNP SARS-CoV-2 vaccines. However, not all cells are easily transfected with RNA-LNPs, requiring inquiries to elucidate the barriers to efficient transfection of cells and screen for possible transfection enhancers. In our study we demonstrate the potential of repurposing Resveratrol, a plant-based polyphenol commonly found in grape skins, to enhance transfection in challenging to transfect primary cells and cell lines while delineating barriers to transfection of these cells. First, we explored RNA-LNP transfection barriers in primary Chronic Lymphocytic Leukemia (CLL) cells, the most common adult leukemia in western populations. Transfection of RNA into CLL cells remains a formidable challenge and a bottleneck for developing targeted therapies for this disease. We transfected primary CLL patient samples with mRNA and siRNA payloads encapsulated in an FDA approved LNP formulation and characterized the transfection. Additionally, we tested the potential of repurposing Caffeic acid, Curcumin and Resveratrol to enhance the transfection of nucleic acids into CLL cells. The results demonstrate that rapid uptake of LNPs is required for successful transfection. Furthermore, we demonstrate that Resveratrol enhances the delivery of both mRNA and siRNA encapsulated in LNPs into primary CLL patient samples, overcoming inter-patient heterogeneity. This study points out the important challenges to consider for efficient RNA therapeutics for CLL patients and advocates the use of Resveratrol in combination with RNA lipid nanoparticles to enhance delivery into CLL cells. Next, we demonstrated the potential of repurposing Resveratrol for enhanced transfection of challenging to transfect murine macrophage cell line and are currently in the process of in-vivo translation of these findings.