Third, chemical modifications of the DNA scaffold could also make it recalcitrant to degradation.
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In addition, a covalently linked base pair between 5-formyluracil and 5-aminocytosine via Schiff base formation has been developed Fig. DNA duplexes containing this base pair are stable under denaturing conditions and dissociate only at high temperatures Another novel strategy that crosslinks duplex DNA to enhance structural stability utilizesan aniline-derived DNA heterobase and hydroxy benzaldehyde. This is similar to an A—T base pair that can be reversibly crosslinked Fig. Another strategy to evade enzymatic cleavage of DNA nano-structures is to use unnatural nucleic acid analogues that have modified chirality such as L-DNA 81 Fig.
These unnatural analogues are not substrates for endo genous nucleases and could prolong nanodevice lifetimes, yet affording essentially identical functionality. Such approaches however, are yet to be embraced widely in the field given the prohibitively high cost of their syntheses. An important property of nanostructured DNA scaffolds is their propensity to induce antibody responses. An example is the use of a tetrahedral DNA nanodevice as an adjuvant in vertebrates that produced antibodies against an antigen of choice Another example is a helix, hollow DNA origami tube, which when coated with CpG motifs potently activated immune cells in a TLR9-dependent manner This has also been observed with CpG-motifs presented on SNA that elicited better antibody responses and tumour regression in mice compared with their ssDNA counterparts Given that such immunostimulatory or immunoregulatory DNA nanodevices outperform unstructured or polymer-coated stimulatory DNA, they could become important in prophylaxis, therapeutics and possibly even transform vaccine biology Conversely, DNA nanodevices could also be designed to potentially suppress immune responses, which would be useful in contexts such as uncontrolled inflammation.
Regulatory T cells are suppressor cells that dampen immune responses and can be elicited using optimized CpG-free, polymer-complexed DNA nanostructures 32 , In addition, single-stranded phosphorothioate oligonucleotides with four TTAGGG motifs can directly bind AIM2 and IFI16 and prevent inflammasome signalling, and may be a starting point to find specific inhibitors of these pathways While the above applications leverage immune responses in complex mammalian systems, simpler invertebrate models offer the power of genetics for more fundamental studies on the interaction of nanostructured DNA scaffolds with the innate immune system.
For example, C. However, the genetically tractable zebrafish Danio rerio , which harbours both an innate and adaptive immune response as well as the IFN-response system, may eventually prove to be a better model system 94 , Importantly, it is also known that not all DNA sequences are equally immunogenic.
Therefore, screens to identify sequences of low or enhanced immunogenicity should better inform nanostructure design to fine-tune immune responses Fig.
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Further, immune responses are likely to be species-specific, as has been observed in the case of differential immunomodulatory effects of DNA on human versus mouse cells We envision that the next generation of biologically smart DNA nano devices would need to incorporate an additional layer of design. These would leverage size and shape information to achieve precise targeting and clearance properties, exploiting sequences with custom-designed host immune responses.
Such nanodevices could act as smart cargo carriers that, as a function of molecular logic, can either be destabilized or remodelled to release their cargo. Although there are rare examples of conditional cargo release from DNA nano-devices albeit in vitro 96 — 98 , there is paucity of information on the effects of DNA sequence, nanostructure size and shape on their immunogenicity and in vivo clearance of the resultant DNA nanostructures in any organism. These data would improve our understanding of basic DNA sequence requirements to develop design criteria that can rationally tune biological nanodevice functionality such as stability or immunogenicity.
Even the latest sequence design programmes 99 , consider only architectural shape and flexibility of DNA nanodevices.
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Such next-generation designer DNA nanodevices with customized host responses would find tantalizing applications in drugdelivery. Given that responses of individual subjects to DNA differ greatly, one can envisage DNA nanodevices engineered for personalized immunotherapy. More excitingly, in the longer term, the delivery of DNA or RNA cargo encoding transcription programs, which bypass the immune system, could be used to remodel synapses to alter learning and memory, or for tissue regeneration, or building organoids from single cells.
To fully harness the potential of the DNA scaffold in vivo, the next layer of design in DNA nanodevices needs strategies to leverage endogenous surveillance mechanisms to maximally tap nano device functionality.
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Insect modulation of host immune responses
Nat Nanotechnol. Author manuscript; available in PMC May PMID: Sunaina Surana , 1 Avinash R.
Avinash R. Copyright notice. See other articles in PMC that cite the published article. Open in a separate window. Figure 1.
Figure 2. Designer DNA nanodevices in vivo A selection of designer DNA nanodevices have been used either as drug-delivery vehicles or diagnostic probes in living systems 2. Figure 3. Figure 4. Outlook and summary We envision that the next generation of biologically smart DNA nano devices would need to incorporate an additional layer of design. Acknowledgements A. Footnotes Contributed by Author contributions All authors contributed equally in writing the manuscript.
References 1. Programmable materials and the nature of the DNA bond. We recommend this paper as an introduction to advances in DNA nanotechnology. Krishnan Y, Bathe M. Designer nucleic acids to probe and program the cell. Trends Cell Biol. Fu Y, He C.blacksmithsurgical.com/t3-assets/humor/mus-your-wheat-free.php
Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis
Nucleic acid modifications with epigenetic significance. Curr Opin Chem Biol. Mobile genetic elements: the agents of open source evolution. Nature Rev Microbiol. Biology of DNA restriction. Microbiol Rev. Comparative genomics of defense systems in archaea and bacteria. Nucleic Acids Res. Adv Drug Deliv Rev. Xu C-X et al.
V-shaped dinuclear Pt II complexes: selective interaction with human telomeric G-quadruplex and significant inhibition towards telomerase. Sci Rep. The i-motif in nucleic acids. Curr Opin Struct Biol. Spherical nucleic acids. J Am Chem Soc. Rothemund PWK.
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