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journal article·2025-03Open access

Exceptional Uptake, Limited Protein Expression: Liver Macrophages Lost in Translation of Synthetic mRNA

Cheng Lin, Adrian Kuzmanović, Nan Wang, Liangliang Liao, Sabrina Ernst, Christian Penners, Alexander Jans, Thomas Hammoor, Petra Bumnuri Stach, Mona Peltzer, Ines Volkert, Elisabeth Zechendorf, Reham Hassan, Maiju Myllys, Christian Liedtke, Andreas Herrmann, Gurudas Chakraborty, Christian Trautwein, Jan Hengstler, Gerhard Müller‐Newen, Junqing Wang, Ahmed Ghallab, Matthias Bartneck

Advanced Science· Volume 12· Issue 9
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Abstract

Abstract Most gene therapies exert their actions via manipulation of hepatocytes (parenchymal cells) and the reasons behind the suboptimal performance of synthetic mRNA in non‐parenchymal cells (NPC) such as Kupffer cells (KC), and liver macrophages, remain unclear. Here, the spatio‐temporal distribution of mRNA encoding enhanced green fluorescent protein (Egfp), siRNA, or both co‐encapsulated into lipid nanoparticles (LNP) in the liver in vivo using real‐time intravital imaging is investigated. Although both KC and hepatocytes demonstrate comparable high and rapid uptake of mRNA‐LNP and siRNA‐LNP in vivo, the translation of Egfp mRNA occurs exclusively in hepatocytes during intravital imaging. Despite attempts such as inhibiting intracellular ribonuclease, substituting uridine bases in mRNA with pseudouridine, and using a different ionizable lipid in the LNP mixture, no substantial increase in Egfp translation by NPC is possible. The investigation reveals that hepatocytes, which are distinct from other liver cells due to their polyploidy, exhibit significantly elevated levels of total RNA and protein, along with a higher proportion of ribosomal protein per individual cell. Consequently, fundamental cellular differences account for the low mRNA translation observed in NPC. The findings therefore suggest that cellular biology imposes a natural limitation on synthetic mRNA translation that is strongly influenced by cellular ploidy.
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Research context

Nanomaterials

OpenAlex topics: RNA Interference and Gene Delivery · Virus-based gene therapy research · RNA Research and Splicing

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Internal Medicine III University Hospital RWTH Aachen Pauwelsstraße 30 52074 Aachen Germany

Department of Rheumatology and Shanghai Institute of Rheumatology Renji Hospital School of Medicine Shanghai Jiao Tong University Shanghai 200240 China

Department of General Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200240 China

Japan Union Hospital of Jilin University 130033 Changchun China

Confocal Microscopy Facility Interdisciplinary Center for Clinical Research IZKF University Hospital RWTH Aachen 52074 Aachen Germany

DWI – Leibniz Institute for Interactive Materials Forckenbeckstraße 50 52074 Aachen Germany

Institute of Technical and Macromolecular Chemistry RWTH Aachen University Worringerweg 2 52074 Aachen Germany

Department of Intensive and Intermediate Care University Hospital RWTH Aachen 52074 Aachen Germany

Leibniz Research Centre for Working Environment and Human Factors 44139 Dortmund Germany

Department of Forensic and Veterinary Toxicology Faculty of Veterinary Medicine South Valley University 83523 Qena Egypt

Institute of Biochemistry and Molecular Biology RWTH Aachen University Pauwelsstraße 30 52074 Aachen Germany

Funding

Deutsche Forschungsgemeinschaft · Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie · Wilhelm Sander-Stiftung · RWTH Aachen University · National Natural Science Foundation of China

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