Issue 12, 2021

Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery

Abstract

Lipid-based nanoparticles (LNPs) for the delivery of mRNA have jumped to the forefront of non-viral gene delivery. Despite this exciting development, poor endosomal escape after LNP cell entry remains an unsolved, rate-limiting bottleneck. Here we report the use of a galectin 8-GFP (Gal8-GFP) cell reporter system to visualize the endosomal escape capabilities of LNP-encapsulated mRNA. LNPs substituted with phytosterols in place of cholesterol exhibited various levels of Gal8 recruitment in the Gal8-GFP reporter system. In live-cell imaging, LNPs containing β-sitosterol (LNP-Sito) showed a 10-fold increase in detectable endosomal perturbation events when compared to the standard cholesterol LNPs (LNP-Chol), suggesting the superior capability of LNP-Sito to escape from endosomal entrapment. Trafficking studies of these LNPs showed strong localization with late endosomes. This highly sensitive and robust Gal8-GFP reporter system can be a valuable tool to elucidate intricacies of LNP trafficking and ephemeral endosomal escape events, enabling advancements in gene delivery.

Graphical abstract: Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery

Supplementary files

Article information

Article type
Paper
Submitted
15 nov 2020
Accepted
27 jan 2021
First published
02 feb 2021

Biomater. Sci., 2021,9, 4289-4300

Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery

M. Herrera, J. Kim, Y. Eygeris, A. Jozic and G. Sahay, Biomater. Sci., 2021, 9, 4289 DOI: 10.1039/D0BM01947J

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