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Интеллектуальная Система Тематического Исследования НАукометрических данных |
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Endosomal escape of delivered mRNA from endosomal recycling tubules visualized at the nanoscaleстатья
Статья опубликована в высокорейтинговом журнале
Статья опубликована в журнале из списка Web of Science и/или Scopus- Авторы: Prasath Paramasivam, Franke Christian, Stöter Martin, Höijer Andreas, Bartesaghi Stefano, Sabirsh Alan, Lindfors Lennart, Arteta Marianna Yanez, Dahlén Anders, Bak Annette, Andersson Shalini, Kalaidzidis Yannis, Bickle Marc, Zerial Marino
- Журнал: Journal of Cell Biology
- Том: 221
- Номер: 2
- Год издания: 2022
- Издательство: Rockefeller University Press
- Местоположение издательства: United States
- DOI: 10.1083/jcb.202110137
- Аннотация: Delivery of exogenous mRNA using lipid nanoparticles (LNPs) is a promising strategy for therapeutics. However, a bottleneck remains in the poor understanding of the parameters that correlate with endosomal escape versus cytotoxicity. To address this problem, we compared the endosomal distribution of six LNP-mRNA formulations of diverse chemical composition and efficacy, similar to those used in mRNA-based vaccines, in primary human adipocytes, fibroblasts, and HeLa cells. Surprisingly, we found that total uptake is not a sufficient predictor of delivery, and different LNPs vary considerably in endosomal distributions. Prolonged uptake impaired endosomal acidification, a sign of cytotoxicity, and caused mRNA to accumulate in compartments defective in cargo transport and unproductive for delivery. In contrast, early endocytic/recycling compartments have the highest probability for mRNA escape. By using super-resolution microscopy, we could resolve a single LNP-mRNA within subendosomal compartments and capture events of mRNA escape from endosomal recycling tubules. Our results change the view of the mechanisms of endosomal escape and define quantitative parameters to guide the development of mRNA formulations toward higher efficacy and lower cytotoxicity.
- Добавил в систему: Калайдзидис Яннис Леонтьевич