Cancer is a leading cause of death worldwide. There are still unmet needs for intracellularly targeted drug delivery system. The emerging platform of RNA Nanotechnology has great promise to improve drug delivery strategies for cancer treatment. The RNA nanotechnology using thermodynamically stable core structure with chemical modifications can overcome conventional cancer therapeutics limitations, provide more specific therapeutic siRNA, miRNA and chemical drug delivery with significantly reduced toxicity and side effects.
The RNA Nanotechnology field is relatively new. The first evidence
showing that RNA Nanoparticles can be constructed using reengineered
RNA molecules by controlled self-assembly was reported in 1998, a study
led by Professor Peixuan Guo.
Milestone 1: Chemical modification improved RNA’s chemical stability
Milestone 2: Thermodynamically stable RNA three-way junction was discovered
Milestone 3: Industrialization of RNA to overcome the barricade of low yield and high cost
Milestone 4: To be evidenced!
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]
Shu D, Shu Y, Haque F, … Guo P. Thermodynamically stable RNA three-way junction for constructing multifunctional nanoparticles for delivery of therapeutics. Nature Nanotechnology 2011;6(10):658-67.[link]
Guo P. The emerging field of RNA nanotechnology. Nature Nanotechnology. 2010;5:833.[link]
-Negative charge disallows nonspecific permeation of negatively charged cell membrane
-Controlled synthesis provides defined structure and stoichiometry
-Multi-valency allows combination therapy and simultaneous targeting and detection
-Targeted delivery allows receptor mediated endocytosis
-Advantageous size (10 – 40 nm)
-Extended in vivo half-life (5-12 hr compared to 15-45 min for siRNA)
-Avoidance of antibody induction (protein-free) allows repeated treatment for chronic diseases
- Favorable pharmacokinetic profile in mice:
Half-life (T1/2) : 5-10 hr compared to 0.25-0.76 hr of siRNA counterpart;
Clearance (Cl): <0.13 l/kg/hr,
Volume of distribution (V(d)): 1.2 l/kg;
Does not induce interferon (IFN) response or cytokine production；
Repeated IV administrations of up to 30 mg/kg do not result in toxicity.
- RNA nanoparticles are classified as chemical drugs rather than biologics. This classification facilitates drug approval.