siRNA-Schizophyllan Complex with Phosphorothioated Polydeoxyadenine
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Solution Overview
Problem
Current siRNA delivery techniques face challenges in achieving effective RNA interference due to instability and immunostimulatory reactions, with existing complexes like schizophyllan and phosphorothioated polydeoxyadenine not forming stable RISC complexes, leading to inadequate therapeutic effects.
Innovation Solution
A nucleic acid-polysaccharide complex is formed by adding phosphorothioated polydeoxyadenine to siRNA, which is then complexed with schizophyllan, allowing for enhanced stability and targeted delivery to Dectin-1 expressing cells, enabling effective RNA interference and immunomodulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phosphorothioated polydeoxyadenine is added to siRNA to enhance stability, then nuclease resistance is improved, but the complex stability with schizophyllan becomes too high preventing RISC complex formation
Solution Approach 1:
The patent changes the chemical parameter of the polydeoxyadenine linkage from phosphorothioate to phosphodiester, which reduces the binding affinity to schizophyllan while maintaining nuclease resistance through the siRNA structure itself, enabling proper RISC complex formation
Solution Approach 2:
The patent removes the phosphorothioate modification from the polydeoxyadenine sequence, extracting this specific chemical modification while retaining the polydeoxyadenine-siRNA-schizophyllan delivery system, thereby resolving the overly stable complex formation issue
2Reliability
If high dosage of unmodified siRNA is administered to achieve effective RNAi, then gene expression inhibition is improved, but immunostimulatory reactions increase
Solution Approach 1:
The patent introduces polydeoxyadenine as an intermediary component that mediates between the siRNA and schizophyllan, forming a delivery complex that protects the siRNA from immunostimulatory reactions while maintaining RNAi activity at lower doses
Solution Approach 2:
The patent creates a composite delivery system consisting of siRNA-polydeoxyadenine-schizophyllan complex, combining multiple components with complementary functions: siRNA for RNAi, polydeoxyadenine for structural support and reduced immunogenicity, and schizophyllan for targeted delivery
3Ease of operation
If passive targeting delivery techniques are used for siRNA, then delivery to target cell is achieved, but target tropism is insufficient
Solution Approach 1:
The patent employs a composite material system where schizophyllan, a polysaccharide with inherent affinity for certain cell types, is combined with siRNA and polydeoxyadenine to create a delivery complex with enhanced target tropism beyond passive targeting
Solution Approach 2:
The patent creates a multi-functional delivery system where the schizophyllan component provides both structural stability and biological targeting capability, while the polydeoxyadenine-siRNA complex provides both protection and RNAi activity
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 complex effectively induces RNAi activity and provides therapeutic benefits, including immunosuppression in transplantation models with reduced side effects and lower siRNA doses, demonstrating improved stability and targeting efficiency.
Implementation Method 1
phosphorothioated polydeoxyadenine can form a stable complex with schizophyllan
Implementation Method 2
a complex of schizophyllan and a polydeoxyadenine-added siRNA has been proposed as a delivery method of an siRNA to a dendritic cell
Implementation Method 3
RNA interference (RNAi) discovered in 1998 has markedly superior efficacy and persistence to conventional antisense methods
Data Source
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AI summary
An object of the present invention is to provide a highly stable nucleic acid-polysaccharide complex of an siRNA and schizophyllan. A nucleic acid-polysaccharide complex is formed by adding polydeoxyadenine in which at least part of the phosphodiester link portion is phosphorothioated to an siRNA and allowing the siRNA and schizophyllan to form a complex.