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. 2019 Sep 24;10:4333. doi: 10.1038/s41467-019-12275-6

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 7 — A hypothetical mechanism explaining the fate of LNP endosomes. a step 1, 2: after the endocytosis of LNPs, lysosomes fuse with early endosomes and cause the acidification of the endosomal environment (pH 5.5–6.2). a step 3: the surface of LNPs is positively charged, drawing LNPs to the inner membrane of the endosomes, which is negatively charged^{9, 57}. This enables the lipid components of LNPs to fuse with the endosomal membrane, allowing the mRNA translocation to the water phase outside the endosomes. Only the mRNA when neutrally charged by ionizable cationic lipids (ratio 1:1 mRNA:lipid) can cross the endosomal membrane. RNA:lipd ratio other than 1:1 would theoretically be unable to cross the endosomal membrane. b In acidic environment (pH 5.8 or 6.6), the mRNA is slightly released from LNPs, whereas at neutral pH (~7.4), the mRNA and lipids are dissociated (The data are shown as standard error of the mean of three replicates). a step 4a: part of the LNP-mRNA that escapes the endosomal membrane and localizes to the cytoplasm could be dissociated from the ionizable lipids because the pH of the cytoplasm is neutral, consistent with the results shown in b). By contrast a step 4b: when LNP-mRNA is transported to the cytoplasmic side of the endosomal membrane, intraluminal vesicles are formed by invagination of the endosomal membrane, and a portion of the LNP-mRNA could be incorporated into these vesicles. a step 4a and 5: since only a 1:1 ratio (neutral) can cross the endosomal membrane and become incorporated into luminal vesicles of endosomes, endo-EVs contained a 1:1 ratio of hEPO mRNA and ionizable lipids. a step 5: the luminal vesicles are then released into the extracellular environment upon the fusion of multivesicular endosomes with the plasma membrane. c Since LNPs with the same ionizable lipids used in this study are currently being utilized in clinical trials and endo-EVs contained hEPO mRNA acquired after the endocytosis of LNPs and delivered to other cells, we postulate that a similar scenario may occur in individuals administered with LNPs, suggesting that part of the mRNA delivery is achieved by such EVs