Self-Assembled DNA Dendrimer Nanoparticle for Efficient Delivery of Immunostimulatory CpG Motifs.

Dendrimer-like DNA nanostructures have attractive properties such as mechanical stability, highly branched nanostructure, customized sizes, and biocompatibility. In this study, we construct programmable DNA dendrimeric nanoparticles as efficient vehicles to deliver immunostimulatory cytosine-phosphate-guanosine (CpG) sequences for activation of the immune response. DNA dendrimers decorated with CpG-containing hairpin-loops triggered stronger immune response characterized by pro-inflammatory cytokines production, in contrast to DNA dendrimers loading linear CpG. After further modification with TAT peptide, a typical cell-penetrating peptide, on the surface of the nanocarriers, CpG loops-loaded DNA dendrimers showed the enhanced cell internalization and cytokines production. The TAT-DNA dendrimer-CpG loops constructs did not affect the viability of immune cells and no detectable cytotoxicity was observed. Our results demonstrate that the DNA dendrimers can serve as designable and safe vehicles for delivery of immune modulators and anticancer drugs.

[1]  Igor L. Medintz,et al.  Evaluating Dye-Labeled DNA Dendrimers for Potential Applications in Molecular Biosensing. , 2017, ACS sensors.

[2]  N. Hanagata.  CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies , 2017, International journal of nanomedicine.

[3]  Zhen Gu,et al.  Inflammation‐Triggered Cancer Immunotherapy by Programmed Delivery of CpG and Anti‐PD1 Antibody , 2016, Advanced materials.

[4]  Jiaxi Wang,et al.  Cell-penetrating peptides as noninvasive transmembrane vectors for the development of novel multifunctional drug-delivery systems. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[5]  Weihong Tan,et al.  Functional nucleic acid-based hydrogels for bioanalytical and biomedical applications. , 2016, Chemical Society reviews.

[6]  P. Prasad,et al.  Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy. , 2016, Chemical reviews.

[7]  Charles M Lieber,et al.  Spontaneous Internalization of Cell Penetrating Peptide-Modified Nanowires into Primary Neurons. , 2016, Nano letters.

[8]  M. Schroff,et al.  Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703 , 2015, Nucleic acid therapeutics.

[9]  H. Sugiyama,et al.  Self-assembling DNA dendrimer for effective delivery of immunostimulatory CpG DNA to immune cells. , 2015, Biomacromolecules.

[10]  Jiye Shi,et al.  Single-particle tracking and modulation of cell entry pathways of a tetrahedral DNA nanostructure in live cells. , 2014, Angewandte Chemie.

[11]  Yifan Lv,et al.  DNA Dendrimer: An Efficient Nanocarrier of Functional Nucleic Acids for Intracellular Molecular Sensing , 2014, ACS nano.

[12]  I. Gursel,et al.  CpG ODN Nanorings Induce IFNα from Plasmacytoid Dendritic Cells and Demonstrate Potent Vaccine Adjuvant Activity , 2014, Science Translational Medicine.

[13]  Jiye Shi,et al.  Self-assembly of poly-adenine-tailed CpG oligonucleotide-gold nanoparticle nanoconjugates with immunostimulatory activity. , 2014, Small.

[14]  Dongsheng Liu,et al.  pH-responsive size-tunable self-assembled DNA dendrimers. , 2012, Angewandte Chemie.

[15]  Hao Yan,et al.  A DNA nanostructure platform for directed assembly of synthetic vaccines. , 2012, Nano letters.

[16]  Tomoki Shiomi,et al.  Design and development of nanosized DNA assemblies in polypod-like structures as efficient vehicles for immunostimulatory CpG motifs to immune cells. , 2012, ACS nano.

[17]  Tim Liedl,et al.  Cellular immunostimulation by CpG-sequence-coated DNA origami structures. , 2011, ACS nano.

[18]  Dan Luo,et al.  Biodegradable CpG DNA hydrogels for sustained delivery of doxorubicin and immunostimulatory signals in tumor-bearing mice. , 2011, Biomaterials.

[19]  Ying K. Tam,et al.  Lipid-based delivery of CpG oligonucleotides enhances immunotherapeutic efficacy. , 2009, Advanced drug delivery reviews.

[20]  K. Sakurai,et al.  Clustered CpG Sequences to Enhance Cytokine Secretion from Macrophages , 2008 .

[21]  R. Coffman,et al.  Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists , 2007, Nature Medicine.

[22]  S. Timmusk,et al.  Structure-Dependent Modulation of Alpha Interferon Production by Porcine Circovirus 2 Oligodeoxyribonucleotide and CpG DNAs in Porcine Peripheral Blood Mononuclear Cells , 2007, Journal of Virology.

[23]  A. Krieg,et al.  Therapeutic potential of Toll-like receptor 9 activation , 2006, Nature Reviews Drug Discovery.

[24]  K. Ishii,et al.  Innate immune recognition of nucleic acids: Beyond toll‐like receptors , 2005, International journal of cancer.

[25]  L. Babiuk,et al.  Strategies for enhancing the immunostimulatory effects of CpG oligodeoxynucleotides. , 2004, Journal of controlled release : official journal of the Controlled Release Society.

[26]  D. Klinman.  Immunotherapeutic uses of CpG oligodeoxynucleotides , 2004, Nature Reviews Immunology.

[27]  J. Sheehan,et al.  Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex by an allosteric mechanism. , 2001, Biochemistry.

[28]  F. Orson,et al.  Role of endogenous endonucleases and tissue site in transfection and CpG-mediated immune activation after naked DNA injection. , 1999, Human gene therapy.

[29]  G. Hartmann,et al.  CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[30]  L. Orgel,et al.  The stability of different forms of double-stranded decoy DNA in serum and nuclear extracts. , 1992, Nucleic acids research.