Drug delivery systems for RNA therapeutics

Paunovska, Kalina; Loughrey, David; Dahlman, James E.

doi:10.1038/s41576-021-00439-4

Cited by 590 publications

(508 citation statements)

References 249 publications

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“…The last five years have witnessed the approval of several oligonucleotides for human use [1,2]. A major success in this field is the development of the active targeting system based in the use of the triantennary GalNAc ligand directly conjugated to the nucleic acid part [32]. This ligand directs the therapeutic oligonucleotides to hepatocytes [12].…”

Section: Discussionmentioning

confidence: 99%

Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes

et al. 2022

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The development of oligonucleotide conjugates for in vivo targeting is one of the most exciting areas for oligonucleotide therapeutics. A major breakthrough in this field was the development of multifunctional GalNAc-oligonucleotides with high affinity to asialoglycoprotein receptors (ASGPR) that directed therapeutic oligonucleotides to hepatocytes. In the present study, we explore the use of G-rich sequences functionalized with one unit of GalNAc at the 3′-end for the formation of tetrameric GalNAc nanostructures upon formation of a parallel G-quadruplex. These compounds are expected to facilitate the synthetic protocols by providing the multifunctionality needed for the binding to ASGPR. To this end, several G-rich oligonucleotides carrying a TGGGGGGT sequence at the 3′-end functionalized with one molecule of N-acetylgalactosamine (GalNAc) were synthesized together with appropriate control sequences. The formation of a self-assembled parallel G-quadruplex was confirmed through various biophysical techniques such as circular dichroism, nuclear magnetic resonance, polyacrylamide electrophoresis and denaturation curves. Binding experiments to ASGPR show that the size and the relative position of the therapeutic cargo are critical for the binding of these nanostructures. The biological properties of the resulting parallel G-quadruplex were evaluated demonstrating the absence of the toxicity in cell lines. The internalization preferences of GalNAc-quadruplexes to hepatic cells were also demonstrated as well as the enhancement of the luciferase inhibition using the luciferase assay in HepG2 cell lines versus HeLa cells. All together, we demonstrate that tetramerization of G-rich oligonucleotide is a novel and simple route to obtain the beneficial effects of multivalent N-acetylgalactosamine functionalization.

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Section: Discussionmentioning

confidence: 99%

Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes

et al. 2022

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“…Another challenge for tissue delivery is oligonucleotide stability in circulation ( Paunovska et al, 2022 ). Much of this issue has been solved, either by encapsulation of the oligonucleotide in an LNP, or by installment of RNA modifications ( Yu et al, 2019 ).…”

Section: Function Of Trfs and Tirsmentioning

confidence: 99%

Function and Therapeutic Implications of tRNA Derived Small RNAs

Wilson

Dutta

2022

Front. Mol. Biosci.

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tRNA derived small RNAs are mainly composed of tRNA fragments (tRFs) and tRNA halves (tiRs). Several functions have been attributed to tRFs and tiRs since their initial characterizations, spanning all aspects of regulation of the Central Dogma: from nascent RNA silencing, to post-transcriptional gene silencing, and finally, to translational regulation. The length distribution, sequence diversity, and multifaceted functions of tRFs and tiRs positions them as attractive new models for small RNA therapeutics. In this review, we will discuss the principles of tRF biogenesis and function in order to highlight their therapeutic potential.

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“…Therefore, the intrinsic cytotoxicity of unmodified PEI originating from the strong cationic charge density and degree of branching represents a serious concern in biomaterial application and clinical use [16,44,51]. In this respect, numerous approaches have been deployed, showing that chemically modified PEI derivatives may overcome some of these shortcomings, being capable of improving in vivo efficacy and tolerability as well as transfection efficiency and targeting ability to specific cells or populations [13,53]. For instance, polyethylene glycol (PEG)-grafted PEI formulation condensing mRNA shows remarkable transgene expression levels in pulmonary immune cells following systemic administration [54], and chemically modified PEI with chondrocyteaffinity peptides [55] or cyclodextrin-PEI conjugates [56] have been demonstrated to be potent and feasible gene carriers in vivo.…”

Section: Opportunitiesmentioning

confidence: 99%

Electrospun-Fibrous-Architecture-Mediated Non-Viral Gene Therapy Drug Delivery in Regenerative Medicine

2022

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Gene-based therapy represents the latest advancement in medical biotechnology. The principle behind this innovative approach is to introduce genetic material into specific cells and tissues to stimulate or inhibit key signaling pathways. Although enormous progress has been achieved in the field of gene-based therapy, challenges connected to some physiological impediments (e.g., low stability or the inability to pass the cell membrane and to transport to the desired intracellular compartments) still obstruct the exploitation of its full potential in clinical practices. The integration of gene delivery technologies with electrospun fibrous architectures represents a potent strategy that may tackle the problems of stability and local gene delivery, being capable to promote a controlled and proficient release and expression of therapeutic genes in the targeted cells, improving the therapeutic outcomes. This review aims to outline the impact of electrospun-fibrous-architecture-mediated gene therapy drug delivery, and it emphatically discusses the latest advancements in their formulation and the therapeutic outcomes of these systems in different fields of regenerative medicine, along with the main challenges faced towards the translation of promising academic results into tangible products with clinical application.

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Drug delivery systems for RNA therapeutics

Cited by 590 publications

References 249 publications

Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes

Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes

Function and Therapeutic Implications of tRNA Derived Small RNAs

Electrospun-Fibrous-Architecture-Mediated Non-Viral Gene Therapy Drug Delivery in Regenerative Medicine

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