High-resolution visualisation of antisense oligonucleotide release from polymers in cells
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....
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| Veröffentlicht in: | Chemical science (Cambridge) 2024-10, Vol.15 (38), p.1569-15697 |
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| creator | King, Jessica J Chen, Kai Evans, Cameron W Norret, Marck Almasri, Ruba Pavlos, Nathan J Hui, Henry YL Lin, Qiongxiang Bhatt, Uditi Young, Stephen G Smith, Nicole M Nikan, Mehran Prestidge, Clive A Jiang, Haibo Iyer, K. Swaminathan |
| description | 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.
We explore polymer-mediated cytosolic delivery of antisense oligonucleotides using NanoSIMS, visualising the internalisation and dissociation of nucleic acid-polymer complexes at the subcellular level. |
| doi_str_mv | 10.1039/d3sc06773d |
| format | Article |
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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.
We explore polymer-mediated cytosolic delivery of antisense oligonucleotides using NanoSIMS, visualising the internalisation and dissociation of nucleic acid-polymer complexes at the subcellular level.</description><identifier>ISSN: 2041-6520</identifier><identifier>EISSN: 2041-6539</identifier><identifier>DOI: 10.1039/d3sc06773d</identifier><identifier>PMID: 39246363</identifier><language>eng</language><publisher>England: Royal Society of Chemistry</publisher><subject>Lipids ; Nucleic acids ; Oligonucleotides ; Polymers ; Reagents ; Secondary ion mass spectrometry ; Translations ; Visualization</subject><ispartof>Chemical science (Cambridge), 2024-10, Vol.15 (38), p.1569-15697</ispartof><rights>This journal is © The Royal Society of Chemistry.</rights><rights>Copyright Royal Society of Chemistry 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c262t-49bd0d87394b3a35b149672d520ffb5eddfdb6932def8c34c7f417796ef12d983</cites><orcidid>0000-0002-2384-4826 ; 0000-0003-2312-9803 ; 0000-0002-5519-8152 ; 0000-0002-0442-6987 ; 0000-0001-9329-4930 ; 0000-0001-5401-7535</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39246363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>King, Jessica J</creatorcontrib><creatorcontrib>Chen, Kai</creatorcontrib><creatorcontrib>Evans, Cameron W</creatorcontrib><creatorcontrib>Norret, Marck</creatorcontrib><creatorcontrib>Almasri, Ruba</creatorcontrib><creatorcontrib>Pavlos, Nathan J</creatorcontrib><creatorcontrib>Hui, Henry YL</creatorcontrib><creatorcontrib>Lin, Qiongxiang</creatorcontrib><creatorcontrib>Bhatt, Uditi</creatorcontrib><creatorcontrib>Young, Stephen G</creatorcontrib><creatorcontrib>Smith, Nicole M</creatorcontrib><creatorcontrib>Nikan, Mehran</creatorcontrib><creatorcontrib>Prestidge, Clive A</creatorcontrib><creatorcontrib>Jiang, Haibo</creatorcontrib><creatorcontrib>Iyer, K. Swaminathan</creatorcontrib><title>High-resolution visualisation of antisense oligonucleotide release from polymers in cells</title><title>Chemical science (Cambridge)</title><addtitle>Chem Sci</addtitle><description>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.
We explore polymer-mediated cytosolic delivery of antisense oligonucleotides using NanoSIMS, visualising the internalisation and dissociation of nucleic acid-polymer complexes at the subcellular level.</description><subject>Lipids</subject><subject>Nucleic acids</subject><subject>Oligonucleotides</subject><subject>Polymers</subject><subject>Reagents</subject><subject>Secondary ion mass spectrometry</subject><subject>Translations</subject><subject>Visualization</subject><issn>2041-6520</issn><issn>2041-6539</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNpdkc9LHDEUx0OxVFEvvVcGvBRhbJI3k2yOZbdVYcGD7aGnYWbyopHMZJs3U9j_vtHVFczl_frw5cs3jH0W_FJwMN8sUM-V1mA_sCPJK1GqGszBvpf8kJ0SPfL8AEQt9Sd2CEZWChQcsT_X_v6hTEgxzJOPY_HP09wGT-3zFF3RjpMnHAmLGPx9HOc-YJy8xSJhwDbvXYpDsYlhO2Ciwo9FjyHQCfvo2kB4-lKP2e-fP34tr8v17dXN8vu67KWSU1mZznK70GCqDlqoO1EZpaXNxp3rarTW2U4ZkBbdooeq164SWhuFTkhrFnDMvu50Nyn-nZGmZvD05KAdMc7UgOCSa5lVM3r-Dn2Mcxqzu0wJsdBKyDpTFzuqT5EooWs2yQ9t2jaCN0-ZNyu4Wz5nvsrw2Yvk3A1o9-hrwhn4sgMS9fvr26fBf-fOhoU</recordid><startdate>20241002</startdate><enddate>20241002</enddate><creator>King, Jessica J</creator><creator>Chen, Kai</creator><creator>Evans, Cameron W</creator><creator>Norret, Marck</creator><creator>Almasri, Ruba</creator><creator>Pavlos, Nathan J</creator><creator>Hui, Henry YL</creator><creator>Lin, Qiongxiang</creator><creator>Bhatt, Uditi</creator><creator>Young, Stephen G</creator><creator>Smith, Nicole M</creator><creator>Nikan, Mehran</creator><creator>Prestidge, Clive A</creator><creator>Jiang, Haibo</creator><creator>Iyer, K. Swaminathan</creator><general>Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2384-4826</orcidid><orcidid>https://orcid.org/0000-0003-2312-9803</orcidid><orcidid>https://orcid.org/0000-0002-5519-8152</orcidid><orcidid>https://orcid.org/0000-0002-0442-6987</orcidid><orcidid>https://orcid.org/0000-0001-9329-4930</orcidid><orcidid>https://orcid.org/0000-0001-5401-7535</orcidid></search><sort><creationdate>20241002</creationdate><title>High-resolution visualisation of antisense oligonucleotide release from polymers in cells</title><author>King, Jessica J ; Chen, Kai ; Evans, Cameron W ; Norret, Marck ; Almasri, Ruba ; Pavlos, Nathan J ; Hui, Henry YL ; Lin, Qiongxiang ; Bhatt, Uditi ; Young, Stephen G ; Smith, Nicole M ; Nikan, Mehran ; Prestidge, Clive A ; Jiang, Haibo ; Iyer, K. 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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.
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| subjects | Lipids Nucleic acids Oligonucleotides Polymers Reagents Secondary ion mass spectrometry Translations Visualization |
| title | High-resolution visualisation of antisense oligonucleotide release from polymers in cells |
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