Modular RNA Nanostructures for High Thermostability
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Solution Overview
Problem
Current RNA nanoparticles face challenges with low loading efficiency and thermostability, leading to dissociation after systemic injection, which limits their effectiveness in delivering active agents for cancer treatment.
Innovation Solution
Development of modular RNA nanostructures composed of 3-9 synthetic RNA oligonucleotides that self-assemble into highly ordered motifs with multiple double-stranded arms, achieving ultra-high thermostability and melting temperatures, allowing for increased loading capacity and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current RNA nanoparticles are used for drug delivery, then they can deliver active agents to cancer cells, but they suffer from low thermostability and dissociation after systemic injection
Solution Approach 1:
The RNA nanoparticle is divided into multiple separate oligonucleotide strands (first oligonucleotide, second oligonucleotide, third oligonucleotide) that self-assemble through complementary base pairing. This segmentation allows each strand to be stable individually while forming a collectively stable structure through multiple interaction interfaces, preventing dissociation after injection.
Solution Approach 2:
The invention creates a composite RNA structure combining multiple different oligonucleotide sequences with distinct functions: a core-forming oligonucleotide, arm-forming oligonucleotides with double-stranded regions, and cargo-carrying capabilities. This composite approach enhances overall thermostability by distributing thermal stress across multiple structural elements and interaction points.
2Quantity of substance
If current RNA nanoparticles are used, then they can deliver drugs, but they have low loading efficiency for active agents
Solution Approach 1:
The RNA nanoparticle structure serves multiple functions simultaneously: the core domain provides structural stability and thermostability, the double-stranded arms enable cargo loading through hybridization, and the overall structure facilitates cellular delivery. This multi-functionality increases loading efficiency without proportionally increasing complexity, as the same structural elements perform multiple roles.
Solution Approach 2:
The cargo molecule is nested within the RNA nanoparticle structure through hybridization of the third oligonucleotide to the double-stranded arms. This nesting allows high loading efficiency by incorporating cargo into the internal structure of the nanoparticle, while the modular arm design keeps the overall complexity manageable through repetitive structural units.
3Temperature
If RNA oligonucleotides form multiple double-stranded arms, then thermostability increases, but manufacturing complexity increases
Solution Approach 1:
The high-melting-temperature structure is achieved through segmentation into multiple oligonucleotide strands with complementary regions. Each strand can be synthesized separately using standard oligonucleotide synthesis methods, then they self-assemble through hybridization to form the stable multi-armed structure. This segmentation enables high thermostability without requiring complex single-molecule synthesis.
Solution Approach 2:
The oligonucleotides self-assemble into the final nanostructure through complementary base pairing without requiring complex external assembly procedures. The sequences are designed to spontaneously form the core and double-stranded arms when mixed, reducing manufacturing complexity while achieving ultra-high thermostability through the self-organized multi-armed structure.
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 modular RNA nanostructures demonstrate enhanced thermostability and loading efficiency, maintaining structural integrity and effectively delivering active agents to cancer cells, thereby improving treatment outcomes.
Implementation Method 1
The at least three synthetic RNA oligonucleotides can be configured to self-assemble to form the modular RNA motif
Implementation Method 2
the at least three synthetic RNA oligonucleotides can form a central core domain and at least three double-stranded arms arranged around the core domain
Implementation Method 3
wherein the melting temperature of the RNA motif can be greater than 65 degrees Celcius
Data Source
AI summary
Disclosed herein are high Tm RNA nanostructures that can be composed of one or more modules or motifs to build RNA nanostructures with or without layers. The RNA nanostructures can have a core domain and three or more double-stranded arms and formulations thereof to conjugate high copy numbers of therapeutics, pH responsive or enzyme cleavable drug cargo. Also described herein is a design strategy for generation of synthetic RNA oligonucleotides that can self assemble into highly thermostable RNA structures. Also described herein are uses of the RNA nanostructures described herein.