Nucleic Acid Nanostructures for Stable Intra-cellular Delivery
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Solution Overview
Problem
Current methods for delivering nucleic acids, such as mRNA, face challenges due to rapid degradation by extracellular enzymes and require complex and costly encapsulation technologies, which are unstable at ambient temperatures, limiting their applicability, especially in developing nations.
Innovation Solution
Development of nucleic acid nanostructures comprising single-stranded nucleic acid sequences that form geometrically predefined higher-order structures with membrane binding moieties for stable and targeted cellular delivery, including RNA-DNA hybrid nanostructures for enhanced biostability and cellular uptake.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional encapsulation technologies are used to protect nucleic acids from degradation, then delivery stability is improved, but device complexity and manufacturing cost increase significantly
Solution Approach 1:
The patent modifies the chemical parameters of nucleic acids by incorporating modified nucleotides (2'-O-methyl, 2'-fluoro, methoxyamine) and phosphorothioate backbone modifications. These parameter changes enhance resistance to nucleases and improve thermal stability without requiring complex encapsulation systems, thereby resolving the contradiction between delivery stability and device complexity
Solution Approach 2:
The patent creates composite nucleic acid structures by combining different modified nucleotide types (2'-O-methyl, 2'-fluoro, methoxyamine) and phosphorothioate modifications within a single nucleic acid molecule. This composite approach provides synergistic protection against degradation while maintaining sequence-specific functionality, achieving reliable delivery without complex encapsulation
2Reliability
If conventional encapsulation technologies are used to protect nucleic acids, then delivery stability is improved, but manufacturing cost increases significantly
Solution Approach 1:
The patent employs chemical modifications at the molecular level (nucleotide and backbone modifications) rather than requiring complex manufacturing processes for encapsulation. These parameter changes can be incorporated during standard nucleic acid synthesis, significantly reducing manufacturing cost while maintaining delivery stability
3Reliability
If conventional encapsulation technologies are used, then nucleic acid protection is improved, but thermal stability at ambient temperatures deteriorates
Solution Approach 1:
The patent introduces phosphorothioate backbone modifications and 2'-modifications that specifically enhance thermal stability through increased bond strength and reduced flexibility. These parameter changes allow the nucleic acids to maintain structural integrity and resistance to degradation at ambient temperatures without requiring cold chain storage
Solution Approach 2:
The combination of different modified nucleotides and phosphorothioate linkages creates a composite structure with enhanced thermal properties. The diverse chemical modifications work synergistically to provide both protection and thermal stability, eliminating the need for temperature-sensitive encapsulation systems
4Ease of manufacture
If naked nucleic acids are used for delivery, then manufacturing simplicity is maintained, but degradation by extracellular enzymes occurs rapidly
Solution Approach 1:
The patent applies chemical modifications (2'-O-methyl, 2'-fluoro, methoxyamine nucleotides and phosphorothioate backbone) that directly increase resistance to nucleases. These parameter changes can be incorporated during standard synthesis processes, maintaining manufacturing simplicity while dramatically improving stability against enzymatic degradation
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The nanostructures provide a stable and effective platform for intra-cellular delivery of nucleic acids, offering improved thermal stability and resistance to nuclease digestion, with selective binding to immune cells and reduced immune response activation, enabling efficient vaccine delivery and immunomodulation.
Implementation Method 1
predictable folding using base-pairing rules
Implementation Method 2
membrane insertion was achieved through equipping the structures' exterior with hydrophobic lipid anchors
Data Source
AI summary
Improved nucleic acid nanostructures provide a platform for stable and effective intra-cellular delivery of nucleic acids, suitably coding nucleic acids such as mRNA or ssDNA. A nucleic acid nanostructure is provided that comprises a first single stranded nucleic acid sequence that defines a scaffold sequence, wherein the scaffold sequence comprises at least one open reading frame that encodes a first gene product; and a plurality of single stranded nucleic acid sequences that define a plurality of staple sequences, wherein the plurality of staple sequences are capable of hybridising with one or more regions of the scaffold sequence in order to induce the formation of a geometrically defined higher order structure. The nanostructure may further comprise at least one membrane binding moiety, wherein the membrane binding moiety is configured to associate with a cell membrane. The nanostructures may be used in pharmaceutical compositions, such as vaccine compositions, and in methods of treating subjects in need thereof.