title: Fabrication of 14 different RNA nanoparticles for specific tumor targeting without accumulation in normal organs.
abstract: Due to structural flexibility, RNase sensitivity, and serum instability, RNA nanoparticles with concrete shapes for in vivo application remain challenging to construct. Here we report the construction of 14 RNA nanoparticles with solid shapes for targeting cancers specifically. These RNA nanoparticles were resistant to RNase degradation, stable in serum for >36 h, and stable in vivo after systemic injection. By applying RNA nanotechnology and exemplifying with these 14 RNA nanoparticles, we have established the technology and developed "toolkits" utilizing a variety of principles to construct RNA architectures with diverse shapes and angles. The structure elements of phi29 motor pRNA were utilized for fabrication of dimers, twins, trimers, triplets, tetramers, quadruplets, pentamers, hexamers, heptamers, and other higher-order oligomers, as well as branched diverse architectures via hand-in-hand, foot-to-foot, and arm-on-arm interactions. These novel RNA nanostructures harbor resourceful functionalities for numerous applications in nanotechnology and medicine. It was found that all incorporated functional modules, such as siRNA, ribozymes, aptamers, and other functionalities, folded correctly and functioned independently within the nanoparticles. The incorporation of all functionalities was achieved prior, but not subsequent, to the assembly of the RNA nanoparticles, thus ensuring the production of homogeneous therapeutic nanoparticles. More importantly, upon systemic injection, these RNA nanoparticles targeted cancer exclusively in vivo without accumulation in normal organs and tissues. These findings open a new territory for cancer targeting and treatment. The versatility and diversity in structure and function derived from one biological RNA molecule implies immense potential concealed within the RNA nanotechnology field.
authors.affiliation: Nanobiotechnology Center, Markey Cancer Center, and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shu
authors.forename: Farzin
authors.initials: F
authors.lastname: Haque
authors.forename: Dan
authors.initials: D
authors.lastname: Shu
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Zhu
authors.forename: Malak
authors.initials: M
authors.lastname: Kotb
authors.forename: Yuri
authors.initials: Y
authors.lastname: Lyubchenko
authors.forename: Peixuan
authors.initials: P
authors.lastname: Guo
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D055029:Inverted Repeat Sequences; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D036103:Nanotechnology / Q000379:methods*; D063347:Native Polyacrylamide Gel Electrophoresis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy*; D059372:Nucleotide Motifs; D012313:RNA / Q000008:administration & dosage* / Q000737:chemistry; D059370:RNA Folding; D020871:RNA Stability; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D012313:RNA
keywords: RNA nanoparticle; RNA nanotechnology; RNA therapeutics; bacteriophage phi29; nanobiotechnology; target delivery