High-resolution visualisation of antisense oligonucleotide release from polymers in cells.

Autor:	King JJ; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Chen K; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Evans CW; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Norret M; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Almasri R; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia.; UniSA Clinical & Health Sciences, University of South Australia Adelaide SA Australia., Pavlos NJ; School of Biomedical Sciences, The University of Western Australia Perth WA 6009 Australia., Hui HY; Translational Cancer Pathology Laboratory, School of Biomedical Sciences, The University of Western Australia Perth WA 6009 Australia., Lin Q; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Bhatt U; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Young SG; Department of Medicine, University of California Los Angeles CA 90095 USA., Smith NM; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia., Nikan M; Ionis Pharmaceuticals, Inc. Carlsbad CA 92010 USA., Prestidge CA; UniSA Clinical & Health Sciences, University of South Australia Adelaide SA Australia., Jiang H; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia.; Department of Chemistry, Faculty of Science, University of Hong Kong Pok Fu Lam Hong Kong hbjiang@hku.hk., Iyer KS; School of Molecular Sciences, The University of Western Australia Perth WA 6009 Australia swaminatha.iyer@uwa.edu.au.; ARC Training Centre for Next-Generation Biomedical Analysis, The University of Western Australia Perth WA 6009 Australia.
Jazyk:	angličtina
Zdroj:	Chemical science [Chem Sci] 2024 Aug 28. Date of Electronic Publication: 2024 Aug 28.
DOI:	10.1039/d3sc06773d
Abstrakt:	Antisense oligonucleotides (ASOs) are a well-established therapeutic modality based on RNA interference, but low cellular uptake, limited ability to direct ASO trafficking, and a range of intracellular barriers to successful activity compromise both gene silencing outcomes and clinical translations. Herein, we demonstrate that polymers can increase ASO internalisation via intracellular trafficking pathways that are distinct from lipid-based delivery reagents. For the first time, we spatially define internalisation and dissociation stages in the polymer-mediated cytosolic delivery of ASOs using Nanoscale Secondary Ion Mass Spectrometry (NanoSIMS), which enables visualisation of ASO localisation at the organelle level. We find that polymer-ASO complexes are imported into cells, from which free ASO enters the cytosol following complex dissociation. This information enables a better understanding of the intracellular trafficking pathways of nucleic acid therapeutics and may be exploited for therapeutic delivery to enhance the effectiveness of nucleic acid therapeutics in the future. Competing Interests: There are no conflicts to declare. (This journal is © The Royal Society of Chemistry.)
Databáze:	MEDLINE
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