Unshielded Lipid Nanoparticle Composition for PEG-Free Nucleic Acid Delivery

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current lipid nanoparticle (LNP) formulations for nucleic acid delivery rely heavily on polyethylene glycol (PEG)-lipids for stability and bioavailability, but these formulations often suffer from immunogenicity and reduced fusogenicity, limiting their effectiveness and safety.

Innovation Solution

The development of unshielded lipid nanoparticles with elevated neutral lipid content, specifically phospholipids, and minimal or no PEG-lipid, which enhances stability, reduces immunogenicity, and improves fusogenicity for effective nucleic acid delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Stability of the object's composition

If PEG-lipid is included in LNP formulations to prevent aggregation and maintain stability, then particle stability and size control are improved, but immunogenicity increases and fusogenicity decreases

Engineering Contradiction:

Improveparticle stabilityVSAvoidimmunogenicity

Core Design Contradiction:

Stability of the object's compositionVSObject-affected harmful factors

Solution Approach 1:

The patent removes PEG-lipid from the LNP formulation entirely, extracting the problematic component that causes immunogenicity while maintaining particle stability through alternative mechanisms involving the ionizable lipid and neutral lipid composition

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the compositional parameters by eliminating PEG-lipid and adjusting the ratios of ionizable lipid (20-40 mol%), neutral lipid (50-70 mol%), and cholesterol (10-20 mol%), thereby altering the particle properties to achieve both stability and reduced immunogenicity

Inventive Principle:

Principle #35Parameter changes

2Stability of the object's composition

If PEG-lipid is included in LNP formulations to prevent aggregation, then particle size control is improved, but fusogenicity decreases

Engineering Contradiction:

Improveparticle size controlVSAvoidfusogenicity

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent removes PEG-lipid from the formulation, extracting the component that hinders membrane fusion while maintaining particle size control through optimized lipid composition and ratio

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent changes the lipid composition parameters, specifically the ratio of ionizable lipid to neutral lipid to cholesterol, to achieve the desired balance between particle size control and fusogenicity without PEG-lipid

Inventive Principle:

Principle #35Parameter changes

3Quantity of substance

If ionizable cationic lipid is used to facilitate nucleic acid association, then complexation efficiency is improved, but particle size increases and polydispersity increases without PEG-lipid

Engineering Contradiction:

Improvenucleic acid complexationVSAvoidparticle size uniformity

Core Design Contradiction:

Quantity of substanceVSManufacturing precision

Solution Approach 1:

The patent optimizes the molar ratio parameters of ionizable lipid (20-40 mol%), neutral lipid (50-70 mol%), and cholesterol (10-20 mol%) to achieve uniform particle size while maintaining effective nucleic acid complexation

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent creates a composite lipid system combining ionizable lipid, neutral lipid, and cholesterol in specific ratios to achieve properties that individual components cannot provide alone, namely uniform particle size with effective nucleic acid binding

Inventive Principle:

Principle #40Composite materials

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

Unshielded LNPs demonstrate improved stability under shearing and oxidative conditions, enhanced extra-hepatic nucleic acid delivery, reduced immunogenicity, and increased fusogenicity, leading to more effective and localized expression of mRNA after intramuscular injection.

Implementation Method 1

the ionizable lipid becomes uncharged and without any electrostatic repulsion, the particles fuse

Methodology Applied

Scientific EffectpH-dependent ionization:

Implementation Method 2

the inclusion of PEG during neutralization of the formulation provides a steric barrier against further fusion

Methodology Applied

Scientific EffectSteric barrier:

Implementation Method 3

after the lipid nanoparticles are taken up by a cell by endocytosis

Methodology Applied

Scientific EffectEndocytosis:

Implementation Method 4

the ability of these lipids to ionize at low pH enables endosomal escape

Methodology Applied

Scientific EffectEndosomal escape:

Data Source

PatentUS12343429B2Method of delivery of DNA or RNA cargo unshielded lipid nanoparticles and compositions thereof

Publication Date: 2025.07.01 NANOVATION THERAPEUTICS INC

AI summary

The present disclosure provides unshielded lipid nanoparticles and a process that enables the production of such unshielded lipid nanoparticles, thereby overcoming previous challenges of making particles without causing aggregation thereof. The lipid nanoparticles comprise a nucleic acid cargo molecule; a sterol or a derivative thereof present at a content of at least 12 mol %; a neutral lipid, such as a phospholipid having a choline head group present at a content of between 22 mol % and 65 mol %; and an ionizable cationic amino lipid present at a content of between 15 mol % and 45 mol %; wherein the lipid nanoparticle is non-sterically stabilized with a hydrophilic polymer-lipid conjugate, or otherwise unshielded and wherein each mol % content is relative to total lipid present in the lipid nanoparticle.