An optimized exosome production strategy for enhanced yield while without sacrificing cargo loading efficiency

Exosome mediated mRNA delivery is a promising strategy for the treatment of multiple diseases. However, the low yield of exosomes is a bottleneck for clinical translation. In this study, we boosted exosome production via simultaneously reducing the expression of genes inhibiting exosome biogenesis a...

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Bibliographic Details
Published in:Journal of nanobiotechnology 2022-10, Vol.20 (1), p.1-463, Article 463
Main Authors: Zhang, Rongxin, Bu, Te, Cao, Ruidan, Li, Zhelong, Wang, Chen, Huang, Bing, Wei, Mengying, Yuan, Lijun, Yang, Guodong
Format: Article
Language:English
Subjects:
Analysis
Arteriosclerosis
Atherosclerosis
Biosynthesis
Blood
Cell culture
Cell membranes
Culture media
Culture media (Biology)
Cytotoxicity
Efficiency
Exosomes
Familial hypercholesterolemia
Fatty liver
Gene expression
Genes
Genetic engineering
Growth
Liver
Localization
Low density lipoprotein receptors
Microscopy
Morphology
mRNA
mRNA cargo
Proteins
Receptor density
Red cell membrane
Steatosis
Toxicity
Translation
Yield
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Summary:Exosome mediated mRNA delivery is a promising strategy for the treatment of multiple diseases. However, the low yield of exosomes is a bottleneck for clinical translation. In this study, we boosted exosome production via simultaneously reducing the expression of genes inhibiting exosome biogenesis and supplementing the culture medium with red cell membrane components. Among the candidate genes, knocking down of Rab4 was identified to have the highest efficacy in promoting exosome biogenesis while without any obvious cytotoxicity. Additionally, supplementing red cell membrane particles (RCMPs) in the culture medium further promoted exosome production. Combination of Rab4 knockdown and RCMP supplement increased exosome yield up to 14-fold. As a proof-of-concept study, low-density lipoprotein receptor (Ldlr) mRNA was forced expressed in the exosome donor cells and passively encapsulated into the exosomes during biogenesis with this strategy. Though exosome production per cell increased, the booster strategy didn't alter the loading efficiency of therapeutic Ldlr mRNA per exosome. Consistently, the therapeutic exosomes derived by the strategy alleviated liver steatosis and atherosclerosis in Ldlr.sup.-/- mice, similar as the exosomes produced by routine methods. Together, the proposed exosome booster strategy conquers the low yield bottleneck to some extent and would certainly facilitate the clinical translation of exosomes.
ISSN:1477-3155
1477-3155
DOI:10.1186/s12951-022-01668-3