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Organelle-Specific Triggered Release of Immunostimulatory Oligonucleotides from Intrinsically Coordinated DNA-Metal-Organic Frameworks with Soluble Exoskeleton
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
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2017 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 139, no 44, p. 15784-15791Article in journal (Refereed) Published
Abstract [en]

DNA has proven of high utility to modulate the surface functionality of metal-organic frameworks (MOFs) for various biomedical applications. Nevertheless, current methods for preparing DNA-MOF nanoparticles rely on either inefficient covalent conjugation or specific modification of oligonucleotides. In this work, we report that unmodified oligonucleotides can be loaded on MOFs with high density (∼2500 strands/particle) via intrinsic, multivalent coordination between DNA backbone phosphate and unsaturated zirconium sites on MOFs. More significantly, surface-bound DNA can be efficiently released in either bulk solution or specific organelles in live cells when free phosphate ions are present. As a proof-of-concept for using this novel type of DNA-MOFs in immunotherapy, we prepared a construct of immunostimulatory DNA-MOFs (isMOFs) by intrinsically coordinating cytosine-phosphate-guanosine (CpG) oligonucleotides on biocompatible zirconium MOF nanoparticles, which was further armed by a protection shell of calcium phosphate (CaP) exoskeleton. We demonstrated that isMOFs exhibited high cellular uptake, organelle specificity, and spatiotemporal control of Toll-like receptors (TLR)-triggered immune responses. When isMOF reached endolysosomes via microtubule-mediated trafficking, the CaP exoskeleton dissolved in the acidic environment and in situ generated free phosphate ions. As a result, CpG was released from isMOFs and stimulated potent immunostimulation in living macrophage cells. Compared with naked CpG-MOF, isMOFs exhibited 83-fold up-regulation in stimulated secretion of cytokines. We thus expect this isMOF design with soluble CaP exoskeleton and an embedded sequential "protect-release" program provides a highly generic approach for intracellular delivery of therapeutic nucleic acids.

Place, publisher, year, edition, pages
American Chemical Society , 2017. Vol. 139, no 44, p. 15784-15791
Keyword [en]
Biocompatibility, Calcium compounds, Crystalline materials, Medical applications, Nanoparticles, Nucleic acids, Oligonucleotides, Organometallics, Acidic environment, Biomedical applications, Intracellular delivery, Metal organic framework, Metalorganic frameworks (MOFs), Spatiotemporal control, Surface functionalities, Toll-like receptors, DNA, calcium phosphate, cytosine, guanosine, immunostimulating agent, interleukin 6, nanoparticle, oligonucleotide, phosphate, toll like receptor 9, tumor necrosis factor, zirconium, acidity, Article, carbon nuclear magnetic resonance, chemical binding, conformation, controlled study, cytokine release, cytotoxicity, exoskeleton, fluorescence spectroscopy, immunostimulation, immunotherapy, interactions with DNA, RAW 264.7 cell line, transmission electron microscopy, upregulation
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Other Basic Medicine
Identifiers
URN: urn:nbn:se:kth:diva-227052DOI: 10.1021/jacs.7b07895Scopus ID: 2-s2.0-85033219489OAI: oai:DiVA.org:kth-227052DiVA, id: diva2:1203575
Note

QC 20180503

Available from: 2018-05-03 Created: 2018-05-03 Last updated: 2018-05-03Bibliographically approved

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Tu, Yaoquan

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