{"title":"Ex Vivo Delivery of mRNA to Immune Cells via a Nonendosomal Route Obviates the Need for Nucleoside Modification","authors":"Bartika Ghoshal, Debajyoti Chakraborty, Manish Nag, Raghavan Varadarajan and Siddharth Jhunjhunwala*, ","doi":"10.1021/acsbiomedchemau.4c0005710.1021/acsbiomedchemau.4c00057","DOIUrl":null,"url":null,"abstract":"<p >Base modification and the use of lipid nanoparticles are thought to be essential for efficient in vivo delivery and expression of mRNA. However, for ex vivo immune cell engineering, the need for either of the two is unclear. Previous reports have suggested that nucleic acids may be efficiently delivered to immune cells ex vivo, through a nonendosomal delivery route, but the need for base modification has not been determined. Herein, we demonstrate that when a nonendosomal delivery method is used, unmodified mRNA performs equally well to the commonly used base-modified mRNA, including the <i>N</i><sup>1</sup> methyl pseudouridine modification, in terms of protein expression and inflammatory response in cells. However, if an endosomal delivery route is used, then <i>N</i><sup>1</sup> methyl pseudouridine modification is necessary for high expression and low inflammatory response, as demonstrated by others as well. Overall, we show that nonendosomal mRNA delivery renders nucleoside modifications nonessential and that unmodified mRNA combined with nonendosomal delivery route may be used for efficient ex vivo mRNA-based engineering of immune cells.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"4 6","pages":"291–299 291–299"},"PeriodicalIF":3.8000,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00057","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Bio & Med Chem Au","FirstCategoryId":"1085","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsbiomedchemau.4c00057","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Ex Vivo Delivery of mRNA to Immune Cells via a Nonendosomal Route Obviates the Need for Nucleoside Modification
Base modification and the use of lipid nanoparticles are thought to be essential for efficient in vivo delivery and expression of mRNA. However, for ex vivo immune cell engineering, the need for either of the two is unclear. Previous reports have suggested that nucleic acids may be efficiently delivered to immune cells ex vivo, through a nonendosomal delivery route, but the need for base modification has not been determined. Herein, we demonstrate that when a nonendosomal delivery method is used, unmodified mRNA performs equally well to the commonly used base-modified mRNA, including the N1 methyl pseudouridine modification, in terms of protein expression and inflammatory response in cells. However, if an endosomal delivery route is used, then N1 methyl pseudouridine modification is necessary for high expression and low inflammatory response, as demonstrated by others as well. Overall, we show that nonendosomal mRNA delivery renders nucleoside modifications nonessential and that unmodified mRNA combined with nonendosomal delivery route may be used for efficient ex vivo mRNA-based engineering of immune cells.
期刊介绍：
ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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