Lipid Nanoparticle mRNA Distribution for Reduced Immunogenicity

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Solution Overview

Problem

Current lipid nanoparticles face challenges in effectively delivering nucleic acids due to issues like low translation levels, immunogenicity, and delivery problems, which limit their therapeutic potential.

Innovation Solution

Designing lipid nanoparticles with specific distributions of components such as ionizable lipids, PEG lipids, and mRNA, where a majority of mRNA is positioned in interior regions and PEG lipids are surface-accessible, to enhance stability, immunogenicity, and intracellular delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If mRNA is delivered using conventional lipid nanoparticles, then delivery to cells is achieved, but immunogenicity increases and translation levels remain low

Engineering Contradiction:

ImprovemRNA delivery efficacyVSAvoidimmunogenicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by creating heterogeneous LNP populations with distinct mRNA distribution patterns. Some LNPs are designed with mRNA primarily in the interior (encapsulated), while others have mRNA at the surface (accessible). This local differentiation of mRNA positioning within different particle subpopulations enables simultaneous protection from immune detection and efficient cellular delivery, resolving the contradiction between reducing immunogenicity and maintaining delivery efficacy.

Inventive Principle:

Principle #3Local quality

2Stability of the object's composition

If PEG lipid half-life is extended to maintain nanoparticle stability, then circulation time increases, but mRNA accessibility and translation efficiency decrease

Engineering Contradiction:

Improvenanoparticle stabilityVSAvoidmRNA translation efficiency

Core Design Contradiction:

Stability of the object's compositionVSProductivity

Solution Approach 1:

The patent employs dynamics by utilizing the time-dependent shedding of PEG lipids from the nanoparticle surface. The PEG lipid half-life is engineered to be within a specific range (0.25-6 hours) so that PEG is initially present to provide stability and prevent opsonization, then gradually sheds over time to reveal accessible mRNA at the particle surface that can be taken up by cells. This dynamic transition from stable encapsulated state to accessible surface state resolves the contradiction between stability and translation efficiency.

Inventive Principle:

Principle #15Dynamics

3Reliability

If mRNA is fully encapsulated in lipid nanoparticles, then protection from degradation is improved, but cellular uptake and translation are reduced

Engineering Contradiction:

ImprovemRNA protection from degradationVSAvoidprotein expression level

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies segmentation by dividing the LNP population into distinct subpopulations with different mRNA localization characteristics. One segment of LNPs contains primarily encapsulated mRNA for protection, while another segment contains surface-accessible mRNA for cellular uptake. This segmentation of the particle population allows each subpopulation to specialize in either protection or delivery, and together they achieve both high protection and high translation efficiency that neither could achieve alone.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS11786607B2RNA formulations

Publication Date: 2023.10.17 MODERNATX INC

AI summary

This disclosure provides improved lipid-based compositions, including lipid nanoparticle compositions, and methods of use thereof for delivering agents in vivo including nucleic acids and proteins.