TY - JOUR
T1 - RNA Origami Nanostructures for Potent and Safe Anticancer Immunotherapy
AU - Qi, Xiaodong
AU - Liu, Xiaowei
AU - Matiski, Lawrence
AU - Rodriguez Del Villar, Ryan
AU - Yip, Theresa
AU - Zhang, Fei
AU - Sokalingam, Sriram
AU - Jiang, Shuoxing
AU - Liu, Li
AU - Yan, Hao
AU - Chang, Yung
PY - 2020/4/28
Y1 - 2020/4/28
N2 - Rapid developments in nucleic acid nanotechnology have enabled the rational design and construction of self-assembling DNA and RNA nanostructures that are highly programmable. We recently developed a replicable single-stranded RNA origami (RNA-OG) technology that allows a long RNA molecule to be programmed to self-assemble into nanostructures of various shapes. Here, we show that such RNA-OG is highly stable in serum/plasma, and we thus exploited its immunostimulatory potential. We demonstrated that the RNA-OG stimulates a potent innate response primarily through a Toll-like receptor 3 (TLR3) pathway. In a murine peritoneal metastatic colon cancer model, intraperitoneally injected RNA-OG induced significant tumor retardation or regression by activating NK- and CD8-dependent antitumor immunity and antagonizing the peritoneal immunosuppressive environment. Unlike polyinosinic/polycytidylic acid (PolyIC), a well-known double-stranded RNA analogue, the RNA-OG treatment did not cause a high level of type-I interferons in the blood nor apparent toxicity upon its systemic administration in the animals. This work establishes the function of RNA-OG as a potent line of TLR3 agonists that are safe and effective for cancer immunotherapy.
AB - Rapid developments in nucleic acid nanotechnology have enabled the rational design and construction of self-assembling DNA and RNA nanostructures that are highly programmable. We recently developed a replicable single-stranded RNA origami (RNA-OG) technology that allows a long RNA molecule to be programmed to self-assemble into nanostructures of various shapes. Here, we show that such RNA-OG is highly stable in serum/plasma, and we thus exploited its immunostimulatory potential. We demonstrated that the RNA-OG stimulates a potent innate response primarily through a Toll-like receptor 3 (TLR3) pathway. In a murine peritoneal metastatic colon cancer model, intraperitoneally injected RNA-OG induced significant tumor retardation or regression by activating NK- and CD8-dependent antitumor immunity and antagonizing the peritoneal immunosuppressive environment. Unlike polyinosinic/polycytidylic acid (PolyIC), a well-known double-stranded RNA analogue, the RNA-OG treatment did not cause a high level of type-I interferons in the blood nor apparent toxicity upon its systemic administration in the animals. This work establishes the function of RNA-OG as a potent line of TLR3 agonists that are safe and effective for cancer immunotherapy.
KW - RNA nanostructures
KW - RNA origami
KW - TLR3 agonists
KW - cancer immunotherapy
KW - peritoneal metastatic colon cancer
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U2 - 10.1021/acsnano.0c00602
DO - 10.1021/acsnano.0c00602
M3 - Article
C2 - 32275389
AN - SCOPUS:85084167615
VL - 14
SP - 4727
EP - 4740
JO - ACS Nano
JF - ACS Nano
SN - 1936-0851
IS - 4
ER -