Ionizable Lipid Nanoparticle Composition for Circular RNA Delivery
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Solution Overview
Problem
Existing nucleic acid therapeutics, such as DNA and viral vectors, face challenges including genetic mutation risks, adverse immune responses, and stability issues with linear mRNAs, while RNA therapeutics face challenges with immunogenicity and delivery efficiency.
Innovation Solution
The development of ionizable lipid nanoparticle compositions that encapsulate circular RNAs, comprising novel ionizable lipids, PEG-modified lipids, and structural lipids, for efficient protein expression in immune cells, with improved circularization efficiency and compatibility with purification methods.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If DNA or viral vectors are used for gene delivery, then genetic information can be inserted into host cells, but there is a risk of unintended insertion into intact genes causing mutations or adverse immune responses
Solution Approach 1:
The invention extracts the harmful elements (DNA integration and viral components) from the gene delivery system and replaces them with circular RNA that operates in the cytoplasm without integrating into the genome, thereby eliminating mutation risks and reducing immune responses
Solution Approach 2:
The invention uses circular RNA as an intermediary carrier that can deliver genetic information without the harmful properties of DNA or viral vectors. The circular RNA structure serves as a safe mediator that achieves gene expression without genomic integration or strong immunogenicity
2Reliability
If linear mRNA is used for RNA therapy, then protein expression can be achieved, but the linear mRNA has limited stability and is prone to degradation
Solution Approach 1:
The invention inverts the conventional linear mRNA structure into a circular configuration. This structural inversion eliminates the vulnerable 5' and 3' ends of linear mRNA that are targets for exonuclease degradation, thereby dramatically improving stability and half-life
Solution Approach 2:
The invention changes the topological parameter of the RNA molecule from linear to circular, which fundamentally alters its degradation kinetics and stability profile, extending the duration of action while maintaining protein expression capability
3Reliability
If circular RNA is used to improve stability, then resistance to exonuclease degradation is achieved, but delivery efficiency and cellular uptake remain challenging
Solution Approach 1:
The invention creates a composite delivery system combining circular RNA with lipid nanoparticles. The lipid nanoparticle component facilitates cellular uptake and delivery, while the circular RNA component provides stability and resistance to degradation, achieving synergistic effects
Solution Approach 2:
The invention nests the circular RNA therapeutic agent inside lipid nanoparticle carriers. This nested structure protects the circular RNA during delivery, enhances cellular uptake, and enables efficient cytoplasmic release while maintaining the stability advantages of the circular structure
4Productivity
If conventional lipid nanoparticles are used for RNA delivery, then delivery efficiency can be improved, but the formulation may not be optimized for circular RNA encapsulation and stability
Solution Approach 1:
The invention optimizes the lipid nanoparticle formulation parameters specifically for circular RNA encapsulation, including lipid composition ratios, ionizable lipid pKa values, and PEG-lipid chain lengths, to enhance both delivery efficiency and encapsulation stability
Solution Approach 2:
The invention develops a universal lipid nanoparticle platform that can effectively encapsulate and deliver circular RNA while maintaining stability. The optimized formulation serves multiple functions: protecting circular RNA, facilitating cellular uptake, and enabling efficient cytoplasmic release
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 compositions achieve high encapsulation efficiency and effective delivery of circular RNAs, enhancing protein expression and stability, while minimizing immune response and genetic integration risks.
Implementation Method 1
The transfer vehicles can comprise ionizable lipid, PEG-modified lipid, and/or structural lipid, thereby forming lipid nanoparticles encapsulating therapeutic agents
Data Source
AI summary
Disclosed herein are novel lipids that can be used in combination with other lipid components, such as helper lipids, structural lipids, and cholesterols, to form lipid nanoparticles for delivery of therapeutic agents, such as nucleic acids (e.g., circular polynucleotides), both in vitro and in vivo.