Stimuli-Responsive Lipid Polymer Particles for Stable RNA Delivery
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Solution Overview
Problem
Clinical translation and commercialization of RNA systems, such as mRNA and saRNA, are restricted by inefficient in vivo delivery, high innate immunogenicity, instability, and limited intracellular protein expression due to endosomal entrapment and catalytic hydrolysis, necessitating new delivery systems that provide targeted and stable delivery.
Innovation Solution
Development of sub-micron particles comprising a lipid structure and amphiphilic polymer chains that respond to external stimuli, encapsulating or conjugating macromolecules like nucleic acids, to enhance stability and targeted intracellular delivery.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional lipid nanoparticles are used for RNA delivery, then transfection efficiency is improved, but stability and immunogenicity worsen
Solution Approach 1:
The patent combines cationic lipids with amphiphilic block copolymers to create composite nanoparticle systems. The copolymers contain hydrophobic segments that interact with the lipid core and hydrophilic segments (such as PEG) that provide steric stabilization and reduced immunogenicity on the surface, thereby improving overall particle stability while maintaining transfection efficiency
Solution Approach 2:
The patent modifies the surface properties of lipid nanoparticles by conjugating PEGylated lipids or copolymers, changing the surface hydrophilicity and charge distribution. This parameter change reduces opsonization and macrophage uptake, improving circulation stability and reducing immunogenicity while preserving cellular uptake capabilities
2Reliability
If RNA systems are delivered in vivo, then therapeutic effect is improved, but delivery efficiency worsens due to endosomal entrapment
Solution Approach 1:
The patent employs pH-responsive lipids and polymers that dynamically change their properties in response to endosomal pH. At physiological pH, the particles maintain stable structures, but upon endosomal acidification, the materials undergo conformational changes or protonation that disrupt the endosomal membrane, enabling RNA escape and improving delivery efficiency
Solution Approach 2:
The patent uses endosomolytic agents such as fusogenic lipids or membrane-disrupting peptides as intermediaries between the protective nanoparticle shell and the RNA payload. These intermediaries are triggered to act at specific pH levels, mediating the disruption of endosomal membranes and facilitating RNA release into the cytoplasm
3Ease of operation
If RNA is stored at room temperature, then ease of distribution is improved, but stability worsens due to degradation
Solution Approach 1:
The patent modifies the chemical structure of RNA by incorporating modified nucleosides (such as pseudouridine or N1-methylpseudouridine) that resist degradation by nucleases. This parameter change in RNA composition enables enhanced thermal stability and extended shelf life at room temperature without compromising immunogenicity or translation efficiency
Solution Approach 2:
The patent formulates RNA with stabilizing excipients such as sugars (trehalose, sucrose), polyols (sorbitol, mannitol), or specialized buffering systems that create a protective matrix around the RNA. This composite formulation approach maintains RNA structural integrity and prevents aggregation during storage at elevated temperatures
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 sub-micron particles facilitate effective cytoplasmic delivery of macromolecular payloads, stabilize formulations for long-term storage at room and tropical temperatures, and eliminate the need for ultra-cold storage, while providing controlled and targeted delivery.
Implementation Method 1
the hydrophilicity of the amphiphilic polymer chains changes in response to an external stimulus
Implementation Method 2
sub-micron particle comprising a first payload molecule, a lipid structure and a plurality of amphiphilic polymer chains surrounding the lipid structure
Data Source
AI summary
The disclosure provides a sub-micron particle comprising a first payload molecule, a lipid structure and a plurality of amphiphilic polymer chains surrounding the lipid structure. The first payload molecule is a macromolecule, optionally a nucleic acid. Additionally, the hydrophobicity of the amphiphilic polymer chains changes in response to an external stimulus.