Journal
NATURE BIOTECHNOLOGY
Volume 27, Issue 10, Pages 925-U88Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.1564
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Funding
- board of governors for City of Hope Medical Center
- Harry Lloyd Charitable Trust
- Keck Foundation
- National Institutes of Health [R01CA122976, R01CA115815, R01CA115674, P50CA107399]
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Efficient delivery of small interfering (si)RNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We show that siRNA synthetically linked to a CpG oligonucleotide agonist of toll-like receptor (TLR)9 targets and silences genes in TLR9(+) myeloid cells and B cells, both of which are key components of the tumor microenvironment. When a CpG-conjugated siRNA that targets the immune suppressor gene Stat3 is injected in mice either locally at the tumor site or intravenously, it enters tumor-associated dendritic cells, macrophages and B cells. Silencing of Stat3 leads to activation of tumor-associated immune cells and ultimately to potent antitumor immune responses. Our findings demonstrate the potential of TLR agonist-siRNA conjugates for targeted gene silencing coupled with TLR stimulation and immune activation in the tumor microenvironment.
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