Arrowtail RNA for Ligand Display on Ginger Exosome-like Nanovesicles to Systemic Deliver siRNA for Cancer Suppression

Abstract

Exosomes have shown increasing potential as delivery vesicles for therapy, but challenges like cost/yield, drug payload, and targeting specificity still exist. Plant derived exosome-like nanoparticles have been reported as a promising substitution and exhibit biocompatibility through oral, intranasal administration; however, systemic delivery of siRNA by exosome-like nanoparticles directly isolated from plants has not been reported. Recently, we reported the control of RNA orientation to decorate human derived exosome with cell targeting ligands for specific delivery of siRNA to tumors. Here, we expand to the application of arrowtail RNA nanoparticles for displaying ligands on ginger derived exosome-like nanovesicles (GDENs) for siRNA delivery and tumor inhibition through IV administration. Cushion ultracentrifugation coupled with equilibrium density gradient ultracentrifugation were used for purifying GDENs that displayed size, density, and morphology similar to human derived exosomes. Folic acid (FA), as a ligand, was displayed on the surface of GDENs for targeted delivery of survivin siRNA to KB cancer models. In vitro gene knockdown efficacy by FA-3WJ/GDENs/siRNA complex was comparable to transfection. We observed inhibition of tumor growth on a xenograft model by intravenous administration, which reveals the potential of GDENs as an economic delivery system for siRNA.

A cost-effective polyethylene glycol-based method for the isolation of functional edible nanoparticles from ginger rhizomes

“…Oral delivery of ginger ENPs protects mice from inflammatory bowel disease and colitis associated colon cancer by suppressing inflammation and restoring intestinal homeostasis 7 . Moreover, ginger derived ENPs have also been exploited as a nanocarrier for targeted delivery of biological cargos, such as plasmid DNA, siRNAs, chemotherapeutic drugs and phytochemicals to unhealthy tissues 4,5,[10][11][12] .…”

<p>Extracellular Vesicles – Advanced Nanocarriers in Cancer Therapy: Progress and Achievements</p>

“…These exosome-like nanovesicles from ginger were able to knockdown the target gene efficiently in vitro and inhibit tumor growth on a xenograft model by intravenous administration. 101 Not limited to laboratory study, EVs derived from plants have been introduced into clinical trials. The researchers from the James Graham Brown Cancer Center used fruit-derived EVs to deliver curcumin to treat cancer patients.…”

Recent Advances in Extracellular Vesicles as Drug Delivery Systems and Their Potential in Precision Medicine

“…Furthermore, this source of EVs may allow for scaling up production in a cost-effective way [ 41 ]. Similarly, ginger roots were used as EV source for administration in mice [ 42 ]. An extensive summary of all sources of EVs that have being used, including those used for in vivo administration, can be found in Table 1 and Table 2 .…”

“…When the EVs were loaded with a therapeutic siRNA against survivin, coupling to folic acid resulted in a higher inhibition of the tumor growth in a mice xenograft model for human epidermoid carcinoma, as compared with vesicles without folic acid on their surface. The increased specificity could be explained based on the interaction between folic acid on the EV surface and the folate receptor in the tumor cells [ 42 ].…”