Lipid Nanoparticle mRNA Composition for Multi-Polypeptide Expression
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Solution Overview
Problem
Existing technologies face challenges in efficiently delivering and translating multiple polypeptides in vivo, particularly due to immunogenicity and stability issues of mRNA, as well as the need for targeted immune responses.
Innovation Solution
The use of individual populations of lipid nanoparticles (LNPs) to deliver and translate at least two manufactured mRNA molecules, each encoding a different polypeptide, including optimized codons and modified bases to enhance stability and minimize immunogenicity, and incorporating ionizable cationic lipids to facilitate delivery and endosomal escape.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If mRNA is administered to enable polypeptide expression, then translation efficiency is improved, but immunogenicity increases causing harmful immune responses
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides within the mRNA sequence. Specifically, uridine residues are replaced with pseudouridine or other modified nucleosides, which alters the immunogenicity parameter of the mRNA while maintaining its translation efficiency. This chemical modification reduces recognition by immune sensors while preserving codon function.
Solution Approach 2:
The patent uses lipid nanoparticles as an intermediary delivery system. The LNP composition includes ionizable cationic lipids that complex with the modified mRNA, protecting it from degradation and facilitating cellular uptake. This intermediary system enables the mRNA to reach target cells without triggering excessive immune responses during delivery.
2Productivity
If multiple mRNA molecules are delivered to express multiple polypeptides, then productivity is improved, but delivery complexity increases
Solution Approach 1:
The patent merges multiple mRNA molecules into a single lipid nanoparticle formulation. The LNP delivery system is designed to co-encapsulate multiple distinct mRNA sequences, each encoding different polypeptides, within the same particulate structure. This combining approach enables simultaneous delivery of multiple genetic payloads through a unified delivery mechanism.
Solution Approach 2:
The lipid nanoparticle formulation exhibits universality by serving as a platform capable of delivering various combinations of mRNA sequences. The same LNP composition and delivery methodology can be applied to express different polypeptide combinations, making the system multi-functional and adaptable to various expression needs without requiring separate delivery systems for each mRNA.
3Duration of action of stationary object
If mRNA stability is increased to enhance expression duration, then duration of action is improved, but immunogenicity may increase
Solution Approach 1:
The patent employs parameter changes through nucleoside modification to decouple stability from immunogenicity. Modified nucleosides such as pseudouridine enhance mRNA stability and resistance to degradation while simultaneously reducing immunogenic recognition. This dual effect allows the mRNA to persist longer in the cellular environment without proportionally increasing immune activation.
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
This approach enables transient and efficient expression of multiple polypeptides, such as SARS-COV-2 spike proteins and antigenic polypeptides, by optimizing mRNA stability and immune response, enhancing translation efficiency and reducing immunogenicity.
Implementation Method 1
an ionizable cationic lipid which attracts an anionic mRNA
Implementation Method 2
is involved in escape of message from an endosome in a cell
Data Source
AI summary
Compositions containing two or more lipid nanoparticles, each containing a different mRNA, are described.