Precursor Lipid Nanoparticle Modification for Stable Nucleic Acid Delivery
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Solution Overview
Problem
The delivery of nucleic acids to cells is hindered by their instability and low cell permeability, and existing lipid-containing nanoparticles lack safety, efficacy, and specificity in targeted delivery.
Innovation Solution
A method involving the mixing of a lipid solution with a nucleic acid solution to form a precursor nanoparticle, followed by the addition of a modifying agent to create a nucleic acid lipid nanoparticle composition, with optional processing steps to enhance stability and delivery efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If nucleic acids are delivered directly to cells, then the delivery process is simple, but the stability and cell permeability are poor
Solution Approach 1:
Lipid nanoparticles serve as intermediary carriers that protect nucleic acids from degradation and facilitate their transport into cells. The lipid bilayer structure encapsulates the nucleic acid payload, providing stability while enabling cellular uptake through endocytosis or membrane fusion mechanisms.
Solution Approach 2:
The invention uses composite lipid nanoparticle structures combining ionizable lipids, PEGylated lipids, and nucleic acids to achieve both stability and cell permeability. The composite material properties enable the system to maintain nucleic acid integrity in circulation while facilitating efficient cellular delivery.
2Ease of operation
If lipid-containing nanoparticles are used for nucleic acid delivery, then cell permeability is improved, but safety and specificity are insufficient
Solution Approach 1:
The lipid nanoparticle composition uses PEGylated lipids concentrated at the surface to reduce immunogenicity and improve circulation time, while ionizable lipids are positioned in the core to enable endosomal escape. This spatial distribution of different lipid qualities optimizes both safety and delivery efficiency.
Solution Approach 2:
The ionizable lipid component changes its charge state in response to pH gradients, remaining neutral at physiological pH to reduce immunogenicity and becoming positively charged in acidic endosomes to facilitate membrane disruption and nucleic acid release, thereby improving specificity.
3Quantity of substance
If existing lipid nanoparticle formulations are used, then nucleic acid encapsulation is achieved, but encapsulation efficiency and therapeutic efficacy are suboptimal
Solution Approach 1:
The patent employs preliminary optimization of lipid composition ratios and formulation conditions to maximize encapsulation efficiency during the nanoparticle formation process. By pre-determining optimal parameters such as lipid-to-nucleic acid ratios and mixing conditions, high encapsulation efficiency is achieved without requiring extensive post-processing.
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 improves the stability and specificity of nucleic acid delivery, enhancing encapsulation efficiency and reducing immunogenicity, thereby increasing therapeutic efficacy.
Implementation Method 1
mixing a lipid solution comprising an ionizable lipid with a solution comprising a nucleic acid thereby forming a precursor nucleic acid lipid nanoparticle
Implementation Method 2
adding a lipid nanoparticle modifier comprising a modifying agent to the precursor nucleic acid lipid nanoparticle thereby forming a modified nucleic acid lipid nanoparticle
Data Source
AI summary
The disclosure features novel methods of producing nucleic acid lipid nanoparticle (LNP) compositions employing a modifying agent after formation of a precursor nucleic acid lipid nanoparticle, the produced compositions thereof, and methods involving the nucleic acid lipid nanoparticles useful in the delivery of therapeutics and/or prophylactics, such as a nucleic acid, to mammalian cells or organs to, for example, to regulate polypeptide, protein, or gene expression.