Stable Nucleic Acid Liquid Formulations via Polymer Condensation
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Solution Overview
Problem
Nucleic acid liquid formulations, particularly those containing DNAs and RNAs, face degradation issues in aqueous solutions due to hydrolysis, oxidation, and enzymatic digestion, necessitating ultra-cold storage and leading to limited shelf life and increased logistical costs.
Innovation Solution
The development of stable nucleic acid liquid formulations using polymer-induced nucleic acid condensation, specifically forming RNA-rich or DNA-rich condensates through macroscopic liquid-liquid phase separation with biocompatible crowding polymers like PEG and cationic polymers, and utilizing specific buffers and excipients to enhance thermostability, allowing for storage and transport at refrigerated or ambient temperatures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleic acid liquid formulations are stored at ultra-cold temperatures, then degradation is reduced, but storage and transportation costs increase
Solution Approach 1:
The patent changes the physical state of nucleic acids from dissolved to condensed form through polymer-induced phase separation. This parameter change allows the formulations to remain stable at refrigerated or ambient temperatures without requiring ultra-cold storage, thereby reducing energy costs while maintaining nucleic acid stability
Solution Approach 2:
The patent introduces polymers as intermediary substances that mediate between the nucleic acids and the storage environment. These polymers induce phase separation and form condensates that protect nucleic acids from degradation, enabling stable storage at higher temperatures without cold-chain requirements
2Reliability
If nucleic acid formulations are frozen or lyophilized to prevent degradation, then shelf life is extended, but LNP aggregation occurs leading to loss of biological activity
Solution Approach 1:
The patent changes the physical state from frozen/lyophilized to condensed liquid form. This parameter change avoids the harmful effects of freezing and drying while still providing stability, preventing LNP aggregation and maintaining biological activity
Solution Approach 2:
The patent converts the natural tendency of nucleic acids to phase separate into a beneficial protective mechanism. By inducing controlled phase separation to form condensates, the system protects against degradation without causing the harmful aggregation that occurs with freezing or lyophilization
3Reliability
If polymer concentration is increased to enhance condensate stability, then nucleic acid protection is improved, but formulation complexity increases
Solution Approach 1:
The patent optimizes polymer concentration parameters to achieve the minimum effective level for condensate formation. By carefully controlling this parameter, the formulation achieves stable condensates without excessive complexity, balancing protection efficacy with formulation simplicity
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 method provides stable nucleic acid formulations that resist degradation at elevated temperatures and enzymatic digestion, extending shelf life and reducing storage and transportation costs by eliminating the need for ultra-cold storage.
Implementation Method 1
forming RNA-rich and/or DNA-rich condensates (e.g., droplets or granules) through macroscopic liquid-liquid phase separation
Data Source
AI summary
Stable nucleic acid liquid formulations and methods of making and using the same are provided. According to some aspects, a method for preparing stable nucleic acid liquid formulations are provided that are resistant to nucleic acid degradation caused by enzyme-independent or enzymatic hydrolysis. In some instances, stable nucleic acid liquid compositions and methods or making the same incorporate the use of at least one of a polymer and/or a salt to form a macroscopic RNA-rich condensate. In other aspects, a method for preparing stable nucleic acid encapsulated lipid nanoparticle (LNP) liquid formulations is provided that are resistant to degradation caused by nucleic acid hydrolysis, LNP leakage, and LNP aggregation. In some instances, stable nucleic acid liquid compositions and methods or making the same incorporate the use of a pair of thermodynamically matching LNP synthesis buffer and LNP product formulation buffer with close-to-equal osmotic pressure and chemical potentials of solution components.