Triphenylphosphonium-modified catiomers enhance in vivo mRNA delivery through stabilized polyion complexation

Nanocarriers based on cationic materials play a central role in the success of mRNA-based therapies. Traditionally, amine-bearing lipids and polymers have been successfully employed for creating mRNA-loaded nanocarriers, though they still present challenges, such as physical and biological instabili...

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Bibliographic Details
Published in:Materials horizons 2024-09, Vol.11 (19), p.4711-4721
Main Authors: Norimatsu, Jumpei, Mizuno, Hayato L, Watanabe, Takayoshi, Obara, Takumi, Nakakido, Makoto, Tsumoto, Kouhei, Cabral, Horacio, Kuroda, Daisuke, Anraku, Yasutaka
Format: Article
Language:English
Subjects:
Amines
Animals
Bioavailability
Cations
Cell Line, Tumor
Complexation
Drug Carriers - chemistry
Female
Gene Transfer Techniques
Humans
Lipids
Mice
Micelles
Nucleic acids
Organophosphorus Compounds - chemistry
Polymers - chemistry
RNA, Messenger - administration & dosage
Self-assembly
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Summary:Nanocarriers based on cationic materials play a central role in the success of mRNA-based therapies. Traditionally, amine-bearing lipids and polymers have been successfully employed for creating mRNA-loaded nanocarriers, though they still present challenges, such as physical and biological instability, limiting both delivery efficiency and therapeutic potential. Non-amine cations could be a promising avenue in addressing these limitations. However, such alternatives remain notably underexplored. Herein, we introduced triphenylphosphonium (TPP) as an alternative cationic moiety for mRNA delivery, leveraging its advantageous properties for nucleic acid complexation. Through the modification of amine-bearing catiomers, we replaced traditional amine-based counterparts with TPP to create innovative polymeric micelles as mRNA nanocarriers. A comprehensive analysis, encompassing physicochemical, thermodynamic, and computational approaches, revealed that the TPP substitution significantly influenced polymer self-assembly, mRNA binding, and the overall stability of mRNA-loaded polymeric micelles. Upon intravenous injection, TPP-bearing micelles demonstrated a remarkable increase in mRNA bioavailability, facilitating efficient protein production in solid tumors. These findings provide a compelling rationale for substituting amines with TPP, emphasizing their potential for advancing mRNA therapeutics.
ISSN:2051-6347
2051-6355
2051-6355
DOI:10.1039/d4mh00325j