Covalent Polymer‐RNA Conjugates for Potent Activation of the RIG‐I Pathway
Abstract: RNA ligands of retinoic acid‐inducible gene I (RIG‐I) are a promising class of oligonucleotide therapeutics with broad potential as antiviral agents, vaccine adjuvants, and cancer immunotherapies. However, their translation has been limited by major drug delivery barriers, including poor cellular uptake, nuclease degradation, and an inability to access the cytosol where RIG‐I is localized. Here this challenge is addressed by engineering nanoparticles that harness covalent conjugation of 5′‐triphospate RNA (3pRNA) to endosome‐destabilizing polymers. Compared to 3pRNA loaded into analogous nanoparticles via electrostatic interactions, it is found that covalent conjugation of 3pRNA improves loading efficiency, enhances immunostimulatory activity, protects against nuclease degradation, and improves serum stability. Additionally, it is found that 3pRNA could be conjugated via either a disulfide or thioether linkage, but that the latter is only permissible if conjugated distal to the 5′‐triphosphate group. Finally, administration of 3pRNA‐polymer conjugates to mice significantly increases type‐I interferon levels relative to analogous carriers that use electrostatic 3pRNA loading. Collectively, these studies have yielded a next‐generation polymeric carrier for in vivo delivery of 3pRNA, while also elucidating new chemical design principles for covalent conjugation of 3pRNA with potential to inform the further development of therapeutics and delivery technologies for pharmacological activation of RIG‐I.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Covalent Polymer‐RNA Conjugates for Potent Activation of the RIG‐I Pathway ; day:03 ; month:05 ; year:2024 ; extent:16
Advanced healthcare materials ; (03.05.2024) (gesamt 16)
- Creator
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Palmer, Christian R.
Pastora, Lucinda E.
Kimmel, Blaise R.
Pagendarm, Hayden M.
Kwiatkowski, Alexander J.
Stone, Payton T.
Arora, Karan
Francini, Nora
Fedorova, Olga
Pyle, Anna M.
Wilson, John T.
- DOI
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10.1002/adhm.202303815
- URN
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urn:nbn:de:101:1-2405031434146.751034272278
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 11:02 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Palmer, Christian R.
- Pastora, Lucinda E.
- Kimmel, Blaise R.
- Pagendarm, Hayden M.
- Kwiatkowski, Alexander J.
- Stone, Payton T.
- Arora, Karan
- Francini, Nora
- Fedorova, Olga
- Pyle, Anna M.
- Wilson, John T.
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