Modulation of biological processes in the nucleus by delivery of DNA oligonucleotides conjugated with gold nanoparticles.
The development of a method that can efficiently deliver nucleic acids into the nucleus of living systems remains one of the key challenges for experimental and therapeutic use of nonbiological gene delivery agents. In the current study, we demonstrate a functionalized gold nanoparticle (AuNP) that can serve as a universal carrier for the delivery of DNA oligonucleotides (oligos) into the nucleus. We designed various types of DNA oligos to redirect alternative splicing of pre-mRNAs, such as MCL-1 and BCL-6, and to sequester transcriptional factors, including estrogen receptor α and p53. We successfully delivered the oligos into the nucleus, resulting in the targeted effects. In addition, injection of the antisense DNAs into a xenograft tumor in a mouse model system resulted in inhibited development of the tumor by redirecting the alternative splicing of the pre-mRNA. Our findings show that these nanoconjugates efficiently load and deliver antisense DNAs to redirect gene splicing or double-stranded DNAs to decoy gene transcription by transcriptional factors into mammalian cells and in vivo animals. Therefore, our lego-like AuNP gene delivery system can be used universally to control different biological processes by modulating nuclear gene expression events in living systems.
Department of Biomedical Science, College of Life Science, CHA University, 222 Yatap-Dong, Seongnam 463-836, South Korea.
Dong-Wook
DW
Kim
Jae-Hong
JH
Kim
Mira
M
Park
Ji-Hyun
JH
Yeom
Hayoung
H
Go
Sudeok
S
Kim
Min Su
MS
Han
Kangseok
K
Lee
Jeehyeon
J
Bae
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001686:Biological Phenomena / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000494:pharmacology*; D016373:DNA, Antisense / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D051379:Mice; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009841:Oligonucleotides / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D016373:DNA, Antisense; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009841:Oligonucleotides; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D006046:Gold; D004247:DNA