期刊
RNA BIOLOGY
卷 8, 期 4, 页码 627-636出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/rna.8.4.15394
关键词
mRNA; uptake; endocytosis; caveolae; lipid rafts; scavenger receptor; lysosome; cancer immunotherapy; vaccine
资金
- Bundesministerium fur Bildung und Forschung (BMBF) [FKZ 0315151]
Insertional mutagenesis and the inherent risk of malignancy compromise the clinical use of DNA-based therapies. Being a transient copy of genetic material, mRNA is a safe alternative, overcoming this limitation. As a prerequisite for the development of efficient mRNA-based therapies, we investigated the cellular uptake and intracellular fate of mRNA for the first time. To this end we determined cell-type, dose and energy dependence of mRNA internalization. Moreover, we employed markers for uptake pathways and cellular compartments to analyze the route of mRNA internalization and its intracellular destination. Finally, we addressed the involvement of receptors and their nature using a competitor-based approach. We found that all cell types tested were amenable to uptake and expression of naked mRNA. Internalization mainly occurred via caveolae/lipid raft-rich membrane domains and involved scavenger-receptor(s). Following endocytosis, mRNA eventually accumulated in lysosomes, while part of it escaped into the cytosol giving rise to protein synthesis. Taken together, our findings provide unprecedented insights into the internalization and trafficking of exogenous mRNA, greatly facilitating the development of effective mRNA-based therapies in the future.
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