Investigation of discrepancies between biodistribution and protein expression in targeted LNP-mediated mRNA delivery
발표자
변용주 (서울대학교)
연구책임자
이혁진 (서울대학교)
공동저자
변용주 (서울대학교), Michaela Jeong (UT Southwestern Medical Center), 이혁진 (서울대학교)
초록
내용
LNPs enable targeted mRNA delivery, but discrepancies between tissue distribution and protein expression limit imaging's predictive value. We compared lung- and liver-targeting LNPs using PET and luciferase reporters. PET showed distinct accumulation, but this was not mirrored in expression levels, revealing a "translational gap." In lung-targeting experiments, ApoE knockdown reduced luciferase expression by ~90% without altering tissue distribution. Since vitronectin knockdown had minimal impact, this reduction isn't due to uptake differences, proving that LNP accumulation alone does not guarantee efficacy. Consequently, our study identifies endosomal escape as the primary bottleneck in mRNA delivery. We focus on post-uptake intracellular trafficking, specifically how ApoE facilitates mRNA release into the cytosol. This provides a mechanistic basis for translation efficiency and guides the rational design of next-generation LNP platforms.