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Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.

ABSTRACT: Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from microbial components. Upon infection, nucleic acid sensing TLRs signal within endosomal compartment triggering the induction of essential proinflammatory cytokines and type I interferons to initiate innate immune responses thereby leading to a critical role in the development of adaptive immune responses. Thus, stimulation of TLRs by nucleic acids is a promising area of research for the development of novel therapeutic strategies against pathogenic infection, allergies, malignant neoplasms and autoimmunity. This review summarizes the therapeutic applications of nucleic acids or nucleic acid analogues through the modulation of TLR signaling pathways.

SUBMITTER: Gosu V

PROVIDER: S-EPMC6269001 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.

Gosu Vijayakumar V Basith Shaherin S Kwon O-Pil OP Choi Sangdun S

Molecules (Basel, Switzerland) 20121114 11

Toll-like receptors (TLRs) belong to a family of innate immune receptors that detect and clear invading microbial pathogens. Specifically intracellular TLRs such as TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids such as double-stranded RNA, single-stranded RNA and CpG DNA respectively derived from microbial components. Upon infection, nucleic acid sensing TLRs signal within endosomal compartment triggering the induction of essential proinflammatory cytokines and type I interferons to initiate ...[more]

PMID: 23151919

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Project description:Liposomal spherical nucleic acids (LSNAs) are a class of nanomaterial used broadly for biomedical applications. Their intrinsic capacity to rapidly enter cells and engage cell surface and intracellular ligands stems from their unique three-dimensional architecture, which consists of densely packed and uniformly oriented oligonucleotides on the surface of a liposomal core. Such structures are promising for therapeutics because they can carry chemical cargo within the lipid core in addition to the nucleic acids that define them, in principle enabling delivery of multiple signals to a single cell. On the basis of these traits, we have designed novel dual-targeting LSNAs that deliver a nucleic acid specific for TLR9 inhibition and a small molecule (TAK-242) that inhibits TLR4. Toll-like receptors (TLRs) play a large role in pathogen recognition and disease initiation, and TLR subtypes are differentially located within the lipid membranes of the cell surface and within intracellular endosomes. Oftentimes, in acute or chronic inflammatory conditions, multiple TLRs are activated, leading to stimulation of distinct, and sometimes overlapping, downstream pathways. As such, these inflammatory conditions may respond to attenuation of more than one initiating receptor. We show that dual targeting LSNAs, comprised of unilamellar liposomal cores, the INH-18 oligonucleotide sequence, and TAK-242 robustly inhibit TLR-9 and TLR-4 respectively, in engineered TLR reporter cells and primary mouse peritoneal macrophages. Importantly, the LSNAs exhibit up to a 10- and a 1000-fold increase, respectively, in TLR inhibition compared to the linear sequence and TAK-242 alone. Moreover, the timing of delivery is shown to be a critical factor in effecting TLR-inhibition, with near-complete TLR-4 inhibition occurring when cells were pretreated with SNAs for 4 h prior to stimulation. The most pronounced effect observed from this approach is the benefit of delivering the small molecule within the SNA via the receptor-mediated internalization pathway common to SNAs.

Project description:Electrospinning is a technique that uses polymer solutions and strong electric fields to produce nano-sized fibers that have wide-ranging applications. We present here an overview of the use of electrospinning to incorporate biological products into nanofibers, including microorganisms, cells, proteins, and nucleic acids. Although the conditions used during electrospinning limit the already problematic viability/stability of such biological products, their effective incorporation into nanofibers has been shown to be feasible. Synthetic polymers have been more frequently applied to make nanofibers than natural polymers. Polymer blends are commonly used to achieve favorable physical properties of nanofibers. The majority of nanofibers that contain biological product have been designed for therapeutic applications. The incorporation of these biological products into nanofibers can promote their stability or viability, and also allow their delivery to a desired tissue or organ. Other applications include plant protection in agriculture, fermentation in the food industry, biocatalytic environmental remediation, and biosensing. Live cells that have been incorporated into nanofibers include bacteria and fungi. Nanofibers have served as scaffolds for stem cells seeded on a surface, to enable their delivery and application in tissue regeneration and wound healing. Viruses incorporated into nanofibers have been used in gene delivery, as well as in therapies against bacterial infections and cancers. Proteins (hormones, growth factors, and enzymes) and nucleic acids (DNA and RNA) have been incorporated into nanofibers, mainly to treat diseases and enhance their stability. To summarize, incorporation of biological products into nanofibers has numerous advantages, such as providing protection and facilitating controlled delivery from a solid form with a large surface area. Future studies should address the challenge of transferring nanofibers with biological products into practical and industrial use.

Dataset Information

Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.

Publications

Therapeutic applications of nucleic acids and their analogues in Toll-like receptor signaling.

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