RNA Origami Nanostructures for Potent and Safe Anticancer Immunotherapy

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.