Hexameric tetrahedral RNA nanostructures
Inventors
Shapiro, Bruce A. • Zakrevsky, Paul J. • Jaeger, Luc
Assignees
University of California San Diego UCSD • US Department of Health and Human Services
Publication Number
US-11666663-B2
Publication Date
2023-06-06
Expiration Date
2039-05-08
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Abstract
Disclosed are nanostructures comprising a ribonucleic acid (RNA) scaffold comprising a hexameric tetrahedral core. The tetrahedral core may comprise four hexameric RNA nanorings linked together. Related pharmaceutical compositions, methods of modulating the expression of a target gene in a mammal, methods of treating or preventing a disease in a mammal, and methods of producing a hexameric tetrahedral RNA nanostructure are also disclosed.
Core Innovation
The invention provides nanostructures comprising a ribonucleic acid (RNA) scaffold with a hexameric tetrahedral core formed by linking four hexameric RNA nanorings. Each nanoring is assembled from six dumbbell-shaped monomers that form kissing loop complexes, creating a hexagonal shape. The tethering of nanorings in a tetrahedral core is achieved via "H"-shaped cross-over monomers containing UA-handle three-way junctions (UAh-3WJs) interconnected by a bridge helix.
The core addresses challenges in the application of RNA nanostructures, particularly the insufficient cellular uptake that limits the functional and therapeutic efficacy of RNA delivery platforms. The hexameric tetrahedral configuration provides increased functional capacity and enhanced cellular uptake, enabling the nanostructure to carry up to twelve monomer arms functionalizable with diverse moieties, including RNA interference substrates.
The nanostructure's tetrahedral geometry and unique configuration of kissing loop sequences allow for programmable, sequence-specific self-assembly and robust structural integrity. The structure retains nanoscale size favorable for therapeutic delivery and is adaptable for functionalization with therapeutic, targeting, or imaging agents. Methods of producing, functionalizing, and administering these nanostructures for gene expression modulation and disease treatment in mammals are also disclosed.
Claims Coverage
The patent discloses three independent claims covering the tetrahedral RNA nanostructure and its composition, detailing the structural elements and assembly.
tetrahedral RNA nanostructure with hexameric core
A tetrahedral nanostructure comprising an RNA scaffold with a core formed by four hexameric RNA nanorings linked together, exhibiting a truncated tetrahedral geometry.
H-shaped cross-over monomers linking nanorings
Linking of the four hexameric RNA nanorings is achieved via 'H'-shaped cross-over monomers, each comprising two UA-handle three-way junctions connected by a 7 base pair bridge to form the 'H' shape.
detailed assembly of tetrahedral core from specified monomers
The hexameric tetrahedral core comprises six cross-over monomers and twelve dumbbell monomers arranged so that sets of three dumbbell and three cross-over monomers form each hexameric nanoring, with each cross-over monomer shared between two nanorings to link them.
The independent claims collectively cover the novel tetrahedral RNA nanostructure comprising linked hexameric nanorings through specialized cross-over monomers, specifying monomer arrangements, structural features such as kissing loops and UAh-3WJs, and methods for functionalization and pharmaceutical composition.
Stated Advantages
The tetrahedral RNA nanostructure has increased functional capacity, allowing up to twelve functional monomer arms.
Enhanced cellular uptake compared to RNA nanostructures lacking the hexameric tetrahedral geometry.
Improved gene silencing efficacy when functionalized with RNA interference substrates.
Maintains a nanoscale size suitable for therapeutic delivery and cellular uptake.
Versatility for future therapeutic development, including multi-gene targeting and incorporation of diagnostic elements.
Documented Applications
Delivery of functional moieties such as ligand binding motifs and gene expression regulators.
Modulation of target gene expression in mammals by administering the RNA nanostructure.
Treating or preventing diseases in mammals, including various cancers and viral diseases, by administering the RNA nanostructure or pharmaceutical composition.
Therapeutic applications targeting genes such as polo-like kinase 1 (PLK1) for cancer treatment.
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