Cationic dynamic covalent polymers for gene transfection

Su, Dandan; Coste, Maëva; Diaconu, Andrei; Barboiu, Mihail; Ulrich, Sébastien

doi:10.1039/d0tb01836h

Cited by 31 publications

(29 citation statements)

References 202 publications

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“…However, LNPs reported a poor endosomal escape ability so a significant amount of RNA cargos were nonfunctional (3,4). Cationic polymers can escape from endosomes via the "proton sponge" effect, but they are covalently linked and usually have low biodegradability and high cytotoxicity (5,6). These limitations make it significantly challenging to have a high efficacy of RNAi therapy and impede its translation into clinics (2).…”

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confidence: 99%

DNA-inspired nanomaterials for enhanced endosomal escape

Lee

Sands

Zhang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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To realize RNA interference (RNAi) therapeutics, it is necessary to deliver therapeutic RNAs (such as small interfering RNA or siRNA) into cell cytoplasm. A major challenge of RNAi therapeutics is the endosomal entrapment of the delivered siRNA. In this study, we developed a family of delivery vehicles called Janus base nanopieces (NPs). They are rod-shaped nanoparticles formed by bundles of Janus base nanotubes (JBNTs) with RNA cargoes incorporated inside via charge interactions. JBNTs are formed by noncovalent interactions of small molecules consisting of a base component mimicking DNA bases and an amino acid side chain. NPs presented many advantages over conventional delivery materials. NPs efficiently entered cells via macropinocytosis similar to lipid nanoparticles while presenting much better endosomal escape ability than lipid nanoparticles; NPs escaped from endosomes via a “proton sponge” effect similar to cationic polymers while presenting significant lower cytotoxicity compared to polymers and lipids due to their noncovalent structures and DNA-mimicking chemistry. In a proof-of-concept experiment, we have shown that NPs are promising candidates for antiviral delivery applications, which may be used for conditions such as COVID-19 in the future.

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mentioning

confidence: 99%

DNA-inspired nanomaterials for enhanced endosomal escape

Lee

Sands

Zhang

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…All aspects of the structure of these cationic lipids have been examined; toxicity has been linked to the cationic head group and its multivalent nature, the length and degree of unsaturation of the hydrophilic domain chains, and the linking functionalities. Efficiency of transfection is related to all these structural features, and variations of each can improve transfection efficiency for the target cell or organ [45,46].…”

Section: Cationic Lipids and Lipid Nanoparticlesmentioning

confidence: 99%

Non-Viral Delivery of RNA Gene Therapy to the Central Nervous System

Hauck

Hecker

2022

Pharmaceutics

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Appropriate gene delivery systems are essential for successful gene therapy in clinical medicine. Lipid-mediated nucleic acid delivery is an alternative to viral vector-mediated gene delivery and has the following advantages. Lipid-mediated delivery of DNA or mRNA is usually more rapid than viral-mediated delivery, offers a larger payload, and has a nearly zero risk of incorporation. Lipid-mediated delivery of DNA or RNA is therefore preferable to viral DNA delivery in those clinical applications that do not require long-term expression for chronic conditions. Delivery of RNA may be preferable to non-viral DNA delivery in some clinical applications, since transit across the nuclear membrane is not necessary, and onset of expression with RNA is therefore even faster than with DNA, although both are faster than most viral vectors. Delivery of RNA to target organ(s) has previously been challenging due to RNA’s rapid degradation in biological systems, but cationic lipids complexed with RNA, as well as lipid nanoparticles (LNPs), have allowed for delivery and expression of the complexed RNA both in vitro and in vivo. This review will focus on the non-viral lipid-mediated delivery of RNAs, including mRNA, siRNA, shRNA, and microRNA, to the central nervous system (CNS), an organ with at least two unique challenges. The CNS contains a large number of slowly dividing or non-dividing cell types and is protected by the blood brain barrier (BBB). In non-dividing cells, RNA-lipid complexes demonstrated increased transfection efficiency relative to DNA transfection. The efficiency, timing of the onset, and duration of expression after transfection may determine which nucleic acid is best for which proposed therapy. Expression can be seen as soon as 1 h after RNA delivery, but duration of expression has been limited to 5–7 h. In contrast, transfection with a DNA lipoplex demonstrates protein expression within 5 h and lasts as long as several weeks after transfection.

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“…Exploiting this principle, peptides have been recently introduced in building blocks that yield, by bottom-up self-assembly, macromolecules such as supramolecular polymers or dynamic covalent polymers. Due to their expressed multivalency, 1, 2 dynamic covalent polymers, as well as supramolecular polymers have become useful tools for the biomolecular recognition of proteins 3,4 and nucleic acids, [5][6][7] for (targeted) delivery, [8][9][10][11] bioimaging, 12 and applications in catalysis. 13,14 This strategy of inserting peptides into selfassembled polymers enables generating dynamic analogues of proteins which, thanks to the reversibility of non-covalent interactions or covalent reactions, can grow and collapse depending on the conditions, exchange building blocks/sequence, all of which greatly contribute to endowing/modulating their function.…”

Section: Introductionmentioning

confidence: 99%