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Multiplexed spatial screening of lipid-based nanoparticles for extrahepatic messenger RNA targeting.

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Title: Multiplexed spatial screening of lipid-based nanoparticles for extrahepatic messenger RNA targeting.
Authors: Enzlein, Thomas1 (AUTHOR), Schumacher, Jens1,2 (AUTHOR) jens.schumacher@biontech.de, Geisel, Alexander1 (AUTHOR), Keller, Florian3 (AUTHOR), Houben, Astrid2 (AUTHOR), Walzer, Kerstin C.2 (AUTHOR), Rittel, Miriam F.1,4 (AUTHOR), Fröhlich, Björn C.1 (AUTHOR), Cairns, James L.1,5 (AUTHOR), Cordes, Jonas1 (AUTHOR), Şahin, Uğur2 (AUTHOR), Rudolf, Rüdiger3,4 (AUTHOR), Haas, Heinrich1,2 (AUTHOR), Schmidt, Stefan1 (AUTHOR), Hopf, Carsten1,4,5 (AUTHOR) c.hopf@th-mannheim.de
Source: Journal of Controlled Release. Apr2026, Vol. 392, pN.PAG-N.PAG. 1p.
Subjects: Nanoparticles, Messenger RNA, Targeted drug delivery, Mass spectrometry, Immunofluorescence, Deuterium compounds
Abstract: Lipid-based and other types of nanoparticles (NPs) enable target- and organ-specific, efficient extrahepatic delivery of synthetic messenger RNA (mRNA) or other cargos in vivo. However, clinical translation of targeting mRNA NP products is hampered by the lack of detailed control of targeting selectivity. Here, we introduce multimodal bioluminescence and mass spectrometry imaging (MSI) for active nanoparticle multiplex screening. It combines luminescence and fluorescence imaging on an organ and cellular level, respectively, as functional readouts of the mRNA payload with direct multiplexed assessment of the tissue distribution of lipids from NPs by MSI. This analytical procedure generates organ-specific multimodal information on NP activity and selectivity. Deuteration allows simultaneous spatial mapping of the distribution of different NPs comprising the identical lipids, here demonstrated using lung- and spleen-targeting lipoplex formulations administered to the same mouse. The combination of molecular histology and immunofluorescence microscopy analysis provides a target cell type-specific readout of the NP. Such detailed information allows to gain more profound insight into structure-function-relationships, and will facilitate pharmaceutical development of next generation NPs for extrahepatic organ-specific targeting. [Display omitted] • Multiplexed MALDI-MSI and single-cell IF screen mRNA NPs in vivo. • MALDI-MSI tracks carrier lipids and maps endogenous spleen microanatomy. • Deuterium-labeled lipids act as MS barcodes for simultaneous tracking. • Spleen-targeted lipoplexes transfect CD169+ marginal zone macrophages. • Simultaneous injection increases throughput and reduces animal use. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:Lipid-based and other types of nanoparticles (NPs) enable target- and organ-specific, efficient extrahepatic delivery of synthetic messenger RNA (mRNA) or other cargos in vivo. However, clinical translation of targeting mRNA NP products is hampered by the lack of detailed control of targeting selectivity. Here, we introduce multimodal bioluminescence and mass spectrometry imaging (MSI) for active nanoparticle multiplex screening. It combines luminescence and fluorescence imaging on an organ and cellular level, respectively, as functional readouts of the mRNA payload with direct multiplexed assessment of the tissue distribution of lipids from NPs by MSI. This analytical procedure generates organ-specific multimodal information on NP activity and selectivity. Deuteration allows simultaneous spatial mapping of the distribution of different NPs comprising the identical lipids, here demonstrated using lung- and spleen-targeting lipoplex formulations administered to the same mouse. The combination of molecular histology and immunofluorescence microscopy analysis provides a target cell type-specific readout of the NP. Such detailed information allows to gain more profound insight into structure-function-relationships, and will facilitate pharmaceutical development of next generation NPs for extrahepatic organ-specific targeting. [Display omitted] • Multiplexed MALDI-MSI and single-cell IF screen mRNA NPs in vivo. • MALDI-MSI tracks carrier lipids and maps endogenous spleen microanatomy. • Deuterium-labeled lipids act as MS barcodes for simultaneous tracking. • Spleen-targeted lipoplexes transfect CD169+ marginal zone macrophages. • Simultaneous injection increases throughput and reduces animal use. [ABSTRACT FROM AUTHOR]
ISSN:01683659
DOI:10.1016/j.jconrel.2026.114728