Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer
Abstract Viral vector and lipid nanoparticle based gene delivery have limitations around spatiotemporal control, transgene packaging size, and vector immune reactivity, compromising translation of nucleic acid (NA) therapeutics. In the emerging field of DNA and particularly RNA‐based gene therapies,...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406545 |
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| author | Jeremy L. Pinyon Georg vonJonquieres Stephen L. Mow Amr Al Abed Keng‐Yin Lai Mathumathi Manoharan Edward N. Crawford Stanley H. Xue Sarah Smith‐Moore Lisa J. Caproni Sarah Milsom Matthias Klugmann Nigel H. Lovell Gary D. Housley |
| author_facet | Jeremy L. Pinyon Georg vonJonquieres Stephen L. Mow Amr Al Abed Keng‐Yin Lai Mathumathi Manoharan Edward N. Crawford Stanley H. Xue Sarah Smith‐Moore Lisa J. Caproni Sarah Milsom Matthias Klugmann Nigel H. Lovell Gary D. Housley |
| author_sort | Jeremy L. Pinyon |
| collection | DOAJ |
| description | Abstract Viral vector and lipid nanoparticle based gene delivery have limitations around spatiotemporal control, transgene packaging size, and vector immune reactivity, compromising translation of nucleic acid (NA) therapeutics. In the emerging field of DNA and particularly RNA‐based gene therapies, vector‐free delivery platforms are identified as a key unmet need. Here, this work addresses these challenges through gene electrotransfer (GET) of “naked” polyanionic DNA/mRNA using a single needle form‐factor which supports “electro‐lens” based compression of the local electric field, and local control of tissue conductivity, enabling single capacitive discharge minimal charge gene delivery. Proof‐of‐concept studies for “single capacitive discharge conductivity‐clamped gene electrotransfer” (SCD‐CC‐GET) deep tissue delivery of naked DNA and mRNA in the mouse hindlimb skeletal muscle achieve stable (>18 month) expression of luciferase reporter synthetic DNA, and mRNA encoding the reporter yield rapid onset (<3 h) high transient expression for several weeks. Delivery of DNAs encoding secreted alkaline phosphatase and Cal/09 influenza virus hemagglutinin antigen generate high systemic circulating recombinant protein levels and antibody titres. The findings support adoption of SCD‐CC‐GET for vaccines and immunotherapies, and extend the utility of this technology to meet the demand for efficient vector‐free, precision, deep tissue delivery of NA therapeutics. |
| format | Article |
| id | doaj-art-03bd1f18c276496fbf9609192702d1b9 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-03bd1f18c276496fbf9609192702d1b92025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202406545Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene ElectrotransferJeremy L. Pinyon0Georg vonJonquieres1Stephen L. Mow2Amr Al Abed3Keng‐Yin Lai4Mathumathi Manoharan5Edward N. Crawford6Stanley H. Xue7Sarah Smith‐Moore8Lisa J. Caproni9Sarah Milsom10Matthias Klugmann11Nigel H. Lovell12Gary D. Housley13Translational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTouchlight Genetics Ltd Lower Sunbury Road Hampton UK TW12 2ERTouchlight Genetics Ltd Lower Sunbury Road Hampton UK TW12 2ERTouchlight Genetics Ltd Lower Sunbury Road Hampton UK TW12 2ERTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaTranslational Neuroscience Facility Department of Physiology School of Biomedical Sciences Graduate School of Biomedical Engineering Tyree Institute for Health Engineering (IHealthE) UNSW Sydney NSW 2052 AustraliaAbstract Viral vector and lipid nanoparticle based gene delivery have limitations around spatiotemporal control, transgene packaging size, and vector immune reactivity, compromising translation of nucleic acid (NA) therapeutics. In the emerging field of DNA and particularly RNA‐based gene therapies, vector‐free delivery platforms are identified as a key unmet need. Here, this work addresses these challenges through gene electrotransfer (GET) of “naked” polyanionic DNA/mRNA using a single needle form‐factor which supports “electro‐lens” based compression of the local electric field, and local control of tissue conductivity, enabling single capacitive discharge minimal charge gene delivery. Proof‐of‐concept studies for “single capacitive discharge conductivity‐clamped gene electrotransfer” (SCD‐CC‐GET) deep tissue delivery of naked DNA and mRNA in the mouse hindlimb skeletal muscle achieve stable (>18 month) expression of luciferase reporter synthetic DNA, and mRNA encoding the reporter yield rapid onset (<3 h) high transient expression for several weeks. Delivery of DNAs encoding secreted alkaline phosphatase and Cal/09 influenza virus hemagglutinin antigen generate high systemic circulating recombinant protein levels and antibody titres. The findings support adoption of SCD‐CC‐GET for vaccines and immunotherapies, and extend the utility of this technology to meet the demand for efficient vector‐free, precision, deep tissue delivery of NA therapeutics.https://doi.org/10.1002/advs.202406545DNA and RNA vaccineselectric field focusingnonviral gene therapynucleic acid electrotransferprecision gene delivery platform |
| spellingShingle | Jeremy L. Pinyon Georg vonJonquieres Stephen L. Mow Amr Al Abed Keng‐Yin Lai Mathumathi Manoharan Edward N. Crawford Stanley H. Xue Sarah Smith‐Moore Lisa J. Caproni Sarah Milsom Matthias Klugmann Nigel H. Lovell Gary D. Housley Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer Advanced Science DNA and RNA vaccines electric field focusing nonviral gene therapy nucleic acid electrotransfer precision gene delivery platform |
| title | Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer |
| title_full | Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer |
| title_fullStr | Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer |
| title_full_unstemmed | Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer |
| title_short | Vector‐Free Deep Tissue Targeting of DNA/RNA Therapeutics via Single Capacitive Discharge Conductivity‐Clamped Gene Electrotransfer |
| title_sort | vector free deep tissue targeting of dna rna therapeutics via single capacitive discharge conductivity clamped gene electrotransfer |
| topic | DNA and RNA vaccines electric field focusing nonviral gene therapy nucleic acid electrotransfer precision gene delivery platform |
| url | https://doi.org/10.1002/advs.202406545 |
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