ExRNA PLATFORM
RNA Nanoparticles Displaying EVs for siRNA Delivery (ExRNA)
SiRNA interferes with specific gene expression that has complementary nucleotide sequences by degrading mRNA. It is the most promising type of RNA therapeutics for currently undruggable disease treatment. The major problem is still the low delivery efficiency of siRNA to target cells.
Our ExRNA platform provides a suitable strategy for siRNA therapeutic development. By harnessing the natural siRNA delivery capabilities of exosomes and the specific targeting properties of RNA nanoparticles, we engineer the exosomes post genesis by displaying RNA nanoparticles on the surface of exosomes for cancer cells. This specifically targeted delivery of therapeutic siRNAs enables new cancer treatment development.
ExRNA Release siRNA in Cytosol Avoiding Endosome Trapping
The pathway of cellular uptake and intracellular trafficking of siRNA therapeutics strongly influences its pharmacological efficacy. The therapeutic effect of siRNA is usually compromised due to entrapment in endosomes after the cells enter. ExRNA enters the cells through direct fusion with the outer cell membrane, and then release its siRNA payload into cell cytosol with high efficiency while avoiding endosome trapping.
Enhanced Targeting Efficiency to Cancer Cells
The RNA nanoparticles are built on an arrow-shaped RNA 3WJ structure harboring: (1) a membrane anchoring molecule at the end of the arrow-tail to display it onto the surface of the exosome’s membrane; (2) an aptamer sequence at one end for enhancing its binding affinity to cancer cells. The ExRNA enhances entry into PSMA positive Prostate cancer LNCaP cells significantly compared to controls.
Efficient Cancer Regression in Mice Model
The ExRNA platform has been validated in mice models for triple-negative breast cancer treatment, prostate cancer treatment, and patient-derived colorectal cancer xenograft mice models. Successful delivery of payload siRNA efficiently regressed tumor growth in mice.
References
Pi F, Binzel D, Lee TJ, …Guo P. Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nature Nanotechnology. 2018 Jan; 13(1):82-89. [link]
Zheng Z, Li Z, Xu C, … Guo P. Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping. J Control Release. 2019 Oct;311-312:43-49. [link]
Li Z, Wang H, Yin H, … Guo P. Arrowtail RNA for Ligand Display on Ginger Exosome-like Nanovesicles to Systemic Deliver siRNA for Cancer Suppression. Sci Rep. 2018 Oct 2;8(1):14644. [link]
