Lining Zheng, PhD
Engineering Molecular Strategies for Lipid Nanoparticle Endosomal Escape
Abstract
RNA therapeutics have huge potential, but their delivery is limited by poor endosomal escape. Lipid nanoparticles (LNPs), the leading RNA carriers, are often trapped in endosomes, with under 2% of RNA reaching the cytosol. Building on my prior work identifying LNP topology and LNP corona proteins as key endosomal escape bottlenecks, my project investigates how proteins—on the endosomal membrane and in the LNP corona—modulate escape. In Aim 1, I will study how corona proteins like vitronectin affect LNP-endosome fusion and escape using fusion assays and live-cell imaging. In Aim 2, I will use large unilamellar vesicles with V-ATPase to model active endosomes and measure how LNPs alter membrane mechanics. My studies will reveal how protein-lipid interactions control delivery and guide rational design of next-generation LNPs. This molecular approach to improving endosomal escape will enhance delivery of RNA, DNA, and proteins, advancing the goals of the PhRMA Drug Delivery Program.
This award not only provides critical funding support for my postdoctoral research but also reinforces my commitment to advancing drug delivery science. My research focuses on unraveling how proteins influence lipid nanoparticle delivery systems, with the goal of improving their intracellular delivery efficiency. This fellowship is especially meaningful to me because it serves as strong validation of my research direction and the impact it can have.
