RNP Platform
RNA Nanotechnology
Our Pharmaceutical Development efforts have revolved around developing RNPs based on miRNA therapeutics and chemical drugs. MicroRNA silences mRNA in order to regulate gene expression. This successfully delivers either 1) tumor suppressor miRNAs or 2) antagonistic oncogenic miRNAs into the cancer cells’ cytoplasm, creating a new class of therapeutics for cancer treatment. Specific cancer cell cytoplasm targeted delivery of miRNA is a major challenge. RNPs are attractive as novel therapeutics for cancer treatment because they exhibit proper physicochemical and biocompatibility properties leading to favorable pharmacokinetics and pharmacodynamics for miRNA therapeutics.
RNA nanotechnology, a concept first proven by Professor Peixuan Guo in 1998 (Mol Cell 1998, and featured in Cell, and 4 papers in Nature Nanotech 2010, 2011, 2018), is defined as the bottom-up self-assembly of nanoscale RNA structures. In RNA nanoparticles, the scaffold, targeting ligand, and the therapeutic agent miRNA or siRNA may consist mainly or entirely of RNA. The thermodynamically stable RNA nanoparticles are designed to have a Tm higher than 80°C and are resistant to nuclease degradation. It can also remain undissociated at ultralow concentrations after being diluted in vivo.
RNPs Target Tumor without Accumulation in Liver and Healthy Organs
RNPs show extraordinary cancer cell targeting properties in vivo, as 1) the nanosized feature helps RNPs accumulate on the tumor through the EPR effect and 2) the ligand on RNPs that targets overexpressed biomarkers of cancer cells facilitates cancer cell penetration through receptor-mediated endocytosis. Mice in vivo experiments showed RNPs specific accumulates to (A) head and neck cancer; (B) gastric cancer, (C) colorectal cancer metastasis after IV injection. The platform has great potential for developing next-generation targeted cancer therapies to overcome the current limitations of traditional cancer therapies.
RNPs Show Favorable PK Profile in Mice
The RNPs can be used as RNA therapeutics for miRNA delivery without the requirement of another auxiliary transfection reagent. Following IV injection of RNPs, about 5% of RNPs accumulate into the tumor within 1hr, and the rest are mainly eliminated from urine. The terminal half-life (T1/2) of RNPs are found to be 5-10 hrs in mice compared to 0.25 hrs using siRNAs. Compared to other nano delivery systems, RNPs showed 10-fold higher delivery efficiency and significantly reduced nonspecific accumulation in the liver or spleen.
RNPs Have Low Toxicity in Mice
The tumor-specific targeted biodistribution profile of RNPs indicates that RNPs will reduce the toxicity of the therapeutic delivery to other healthy organs. In repeated dose toxicity tests in mice, after treating mice by IV injection every 48hrs for 7 days with RNPs, up to 30mg/kg, there were no gross pathology differences or enlargements in liver, kidney, and spleens. Compared to the treatment group with controls, there was no obvious change in clinical pathology analysis.
Milestones in RNA Nanotechnology Development
The first evidence showing that RNA Nanoparticles can be constructed using re-engineered RNA molecules by controlled self-assembly was reported in 1998. (Guo et al, Mol Cell, Featured in Cell).
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: Toxicity and immunogenicity
Milestone 5: To be evidenced!
References
Guo S, Vieweger M, Zhang K,… Guo P. Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy. Nature Communications. 2020 Feb.[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]
