Peixuan Guo

Center for RNA Nanobiotechnology and Nanomedicine; College of Pharmacy; the Ohio State University, Columbus, Ohio 43210, US

Title:

The physicochemical property of motile and thermostable while deformable RNA nanoparticles as anionic materials for spontaneous cancer targeting with undetectable toxicit

Abstract:

Besides mRNA, rRNA, and tRNA, cells contain many other noncoding RNA that display critical roles in the regulation of cellular functions. Human genome sequencing revealed that the majority of human genome codes for non-coding RNAs. The dynamic nature and the near-neighbor principle of RNA result in its motile and deformative behavior. These conformational transitions such as the change of base-pairing, breathing within complemented strands, and pseudoknot formation at the 2D level as well as the induced-fit and conformational capture at the 3D level are important for their biological functions including regulation, translation, and catalysis. RNA is a living material.

RNA nanotechnology is the bottom-up self-assembly of nanometer-scale architectures, resembling LEGOs, composed mainly of RNA. The ideal building material should be: 1) versatile and controllable in shape and stoichiometry; 2) spontaneously self-assemble; and 3) thermodynamic, chemic, and enzymatic stable with a long shelf-life. RNA building blocks exhibit each of the above. RNA is a polynucleic acid making it a polymer and its negative charge prevents nonspecific binding to negatively charged cell membranes. The thermostability makes it suitable for logic gates, resistive memory, sensor setups, and NEM devices. RNA can be designed and manipulated with a level of simplicity of DNA while displaying versatile structure and enzyme activity of proteins. RNA can fold into single-stranded loops or bulges to serve as mounting dovetails for inter-molecular or domain interactions without external linking dowels. RNA nanoparticles display rubber- and amoeba-like properties and are stretchable and shrinkable through multiple repeats, leading to enhanced tumor targeting and fast renal excretion to reduce toxicities. RNA will be the third milestone in pharmaceutical drug development.

We have recently reported that the deformative property of RNA nanoparticles enhances their penetration through the leaky blood vessels of cancers which leads to highly efficient tumor accumulation. This special deformative property also enables RNA nanoparticles to pass the glomerulus, overcoming the filtration size limit, resulting in fast renal excretion and rapid body clearance, thus low or no toxicity. The biodistribution of RNA nanoparticles can be further improved by the incorporation of ligands for cancer targeting. In addition to the favorable biodistribution profiles, RNA nanoparticles possess other properties including self-assembly, negative charge, programmability, and multivalency; making it a great material for pharmaceutical applications. The intrinsic negative charge of RNA nanoparticles decreases the toxicity of drugs by preventing nonspecific binding to the negatively charged cell membrane and enhancing the solubility of hydrophobic drugs. The polyvalent property of RNA nanoparticles allows the multi-functionalization which can be applied to overcome drug resistance.

Bio:

            Dr. Guo, a fellow of the National Academy of Inventors, is the pioneer of RNA nanotechnology, has held three endowed chair positions at three different prestigious universities, and currently is the Sylvan G. Frank Endowed Chair in Pharmaceutics and Drug Delivery and the director of the Center for RNA Nanobiotechnology and Nanomedicine at The Ohio State University (OSU). He is the president of the International Society of RNA Nanotech and Nanomedicine. He received his Ph.D. from the University of Minnesota and conducted his postdoctoral training at NIH under Bernard Moss. He joined Purdue University in 1990, tenured in 1993 and became a full professor in 1997, honored as a Purdue Distinguished Faculty Scholar in 1998. He served as the Director of the NIH Nanomedcine Develoment Center (NDC) from 2006-2011,was the Director of NCI Cancer Nanotech Platform Partnership Program from 2012-2017.

         Regarding Dr. Guo’s invention, he first proposed the idea that a large number of previously undiscovered small RNA exist in cells called sRNA (Guo P et al. A small viral RNA is required for in vitro packaging of bacteriophage phi29 DNA. Science 1987; 236: 690); constructed 1st viral DNA packaging motor (PNAS 1986); discovered phi29 motor pRNA (Science, 1987); proved the concept of RNA nanotechnology (Mol Cell 1998, featured in Cell,1998; 4 papers in Nat Nanotechnol 2009, 2010, 2011, 2018; Nature Comm, 2019); he invented a novel method for the production of the vaccinia virus mRNA capping enzyme (PNAS, 1990 ,7:4023) that are used currently as an essential component for the production of COVID-19 mRNA vaccine; his team invented a patented method for the production of COVID-19 mRNA vaccine (see List of Patents)   invented a method for the use of TIRF System to count single-fluorophores molecules (EMBOJ, 2007); invented a unique method for single pore sensing by incorporating phi29 motor channel into the membrane (Nat Nanotechnol, 2009); discovered a 3rd class of biomotor using revolving mechanism without rotation; discovered that RNA is like rubber and amoeba with unusually high efficiency for passive tumor targeting and regression with quick kidney clearance, thus undetectable toxicity; he invented the methods to use RNA nanotechnology to make the insoluble and toxic cancer drugs soluble and nontoxic; he invented RNA nanotechnology to decorate exosomes with a ligand for cancer targeting using the directionality of antibody-like (i.e., Y-shaped) RNA arrow-tail (Nat Nanotechnol, 2017); he invented method for the delivery of RNAi to the cytosol of cancer cells without endosome trapping; his team invented Exojuice for exosome purification with a simple one step by combination of zonal and density gradient. All these invention has enable his team to achieve the treatment of liver cancer, lung cancer, brain cancer, colorectal cancer, breast cancer; stomach cancer, and prostate cancer in preclinical trials (see publication list and news release). ExonanoRNA LLC is actively working toward clinical trials for the treatment of these cancers. 

         Dr. Guo has received many honors including the Pfizer Distinguished Faculty Award, Purdue Faculty Scholar Award, Lions Club Cancer Research Award, Purdue Seed Award (three times), and University of Cincinnati Research Award. He has been recognized as a Distinguished Alumni of the University of Minnesota, Distinguished Chinese Alumni of the University of Minnesota during its 100 year celebration; and named the “Innovator of the Year” by OSU in April of 2021. Dr. Guo is an editor or editorial board member of 7 different scientific journals and has been reported on numerous times by TV such as ABC and NBC, featured by media outlets of NIH, NSF, MSNBC, NCI, and ScienceNow. He was previously a member of two prominent National Nanotechnology Initiatives by NSF, NIH, National Council of Nanotechnology and NIST; two NIH steering committees in NDC and Extracellular RNA.