Nucleic Acid Composition for Endosomal TLR3 Delivery
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Solution Overview
Problem
Current cancer immunotherapy adjuvants face challenges in delivering nucleic acids to endosomal TLR3 effectively, leading to insufficient adjuvanticity and potential side effects from strong TLR3 agonists like poly IC, which cause cytokine storms.
Innovation Solution
A nucleic acid composition comprising a single-stranded DNA linked to a double-stranded RNA capable of activating TLR3, specifically designed to be delivered to endosomes of dendritic cells, utilizing specific base sequences and lengths to enhance immune responses with reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If poly IC is used as a TLR3 agonist adjuvant, then strong adjuvanticity is achieved, but side effects such as cytokine storm occur
Solution Approach 1:
The patent divides the single-stranded DNA and double-stranded RNA into separate molecular entities that function independently but synergistically. The ssDNA component (15-30 nucleotides) targets TLR9 to modulate immune response, while the dsRNA component (40-200 base pairs) targets TLR3 for adjuvanticity. This segmentation allows each component to be optimized for its specific function while reducing overall toxicity.
Solution Approach 2:
The patent creates a composite nucleic acid molecule consisting of ssDNA and dsRNA linked together. This composite structure combines the immunomodulatory properties of TLR9-activating DNA with the adjuvanticity of TLR3-activating RNA, achieving enhanced adjuvanticity with reduced side effects compared to poly IC alone.
2Reliability
If diRNA is administered extracellularly to activate TLR3, then adjuvant effect is achieved, but delivery to endosomal TLR3 is insufficient
Solution Approach 1:
The patent introduces single-stranded DNA as an intermediary molecule that facilitates the delivery of dsRNA to endosomal TLR3. The ssDNA component is designed to be internalized into dendritic cells and deliver the linked dsRNA to the endosomal compartment where TLR3 is located, overcoming the delivery barrier that limits extracellular diRNA administration.
Solution Approach 2:
The patent optimizes specific parameters of the nucleic acid components: ssDNA length (15-30 nucleotides), dsRNA length (40-200 base pairs), and their linkage structure. These parameter changes enhance the molecule's ability to be internalized by dendritic cells and delivered to endosomes, improving delivery efficiency while maintaining adjuvanticity.
3Reliability
If strong TLR3 agonists are used to enhance immune response, then adjuvanticity is improved, but harmful side effects increase
Solution Approach 1:
The patent applies local quality by designing the ssDNA and dsRNA components with specific local characteristics: the ssDNA contains specific base sequences (15-30 nucleotides) that target TLR9 with moderate activation, while the dsRNA (40-200 base pairs) targets TLR3. This localized optimization of each component's properties allows for controlled immune activation at specific sites (TLR9 and TLR3) rather than overwhelming systemic activation.
Solution Approach 2:
The patent employs preliminary anti-action by using the ssDNA component to pre-modulate the immune system through TLR9 before the dsRNA component activates TLR3. This preliminary modulation creates a more controlled immune environment that can handle the TLR3 activation without excessive cytokine production, thereby preventing cytokine storm while maintaining adjuvanticity.
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 nucleic acid composition effectively activates immune responses by enhancing IFN-β expression, activating NK cells, and inducing cytotoxic T cells, demonstrating strong tumor-regression effects with minimal side effects, making it suitable as an immunostimulant and cancer therapeutic agent.
Implementation Method 1
the single-stranded DNA is to be delivered to endosomes of dendritic cells
Implementation Method 2
a double-stranded RNA capable of activating TLR3
Implementation Method 3
enhancing IFN-β expression, activating NK cells, and inducing cytotoxic T cells
Data Source
Figure 1~2
Figure 3(a)~3(d)
Figure 4(a)~4(e)
AI summary
The disclosed nucleic acid at least containing a single-stranded DNA to be delivered to endosomes of dendritic cells and a double-stranded RNA capable of activating TLR3 can be delivered to endosomal TLR3 and has a strong adjuvanticity with few side effects, and therefore is useful as an active ingredient of immunostimulants, vaccine adjuvants, cancer therapeutic agents and the like.