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Nat Biotechnol. 2009 Oct;27(10):925-32. doi: 10.1038/nbt.1564. Epub 2009 Sep 13.

In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses.

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1
Department of Cancer Immunotherapeutics, Beckman Research Institute at City of Hope, Duarte, California, USA.

Abstract

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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PMID:
19749770
PMCID:
PMC2846721
DOI:
10.1038/nbt.1564
[Indexed for MEDLINE]
Free PMC Article

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