Biodegradable Ionizable Lipids for Rapid LNP Clearance

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Solution Overview

Problem

Existing cationic lipids with geminal dialkyl structures degrade slowly in the liver, making them unsuitable for applications requiring accelerated metabolism in vivo, and there is a need for new lipid molecules to address the diverse delivery requirements of different nucleic acid substances and targets in gene therapy.

Innovation Solution

Development of a new class of ionizable cationic lipid compounds with biodegradable groups in the tail chain, enhancing metabolism and reducing toxicity, which are incorporated into lipid nanoparticles for efficient delivery of biologically active substances.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If cationic lipids with geminal dialkyl structures are used, then delivery efficiency is improved, but metabolism rate deteriorates (degrades slowly in the liver)

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidmetabolism rate

Core Design Contradiction:

ProductivityVSDuration of action of moving object

Solution Approach 1:

The lipid molecule is segmented into functional modules: a cationic head group for delivery efficiency and a biodegradable tail chain (containing ester or amide bonds) for controlled metabolism. This segmentation allows independent optimization of delivery performance and metabolic properties.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent modifies the chemical parameters of the lipid tail chain by introducing biodegradable functional groups (ester, amide bonds) and adjusting chain length and saturation. These parameter changes enable the lipid to be metabolized by liver enzymes while maintaining delivery efficiency.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If cationic lipids are used for nucleic acid delivery, then delivery efficiency is improved, but toxicity increases

Engineering Contradiction:

Improvedelivery efficiencyVSAvoidtoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The lipid nanoparticle is designed as a transient delivery vehicle that performs its function and then degrades completely through biodegradable tail chains. This disposable approach eliminates long-term toxicity accumulation while maintaining high delivery efficiency during the therapeutic window.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent converts the potential harm of persistent cationic lipids (toxicity) into a benefit by incorporating biodegradable bonds that enable controlled metabolism. The same structural features that provide delivery efficiency are modified to ensure safe elimination, turning a harmful persistence property into a beneficial transient property.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Object-affected harmful factors

If lipid nanoparticles are designed for rapid metabolism, then safety is improved, but delivery efficiency may deteriorate

Engineering Contradiction:

ImprovesafetyVSAvoiddelivery efficiency

Core Design Contradiction:

Object-affected harmful factorsVSProductivity

Solution Approach 1:

The lipid molecule exhibits local quality differentiation: the head group region maintains cationic character for efficient nucleic acid binding and cellular uptake, while the tail chain region incorporates biodegradable bonds for controlled metabolism. This spatial differentiation of properties allows simultaneous optimization of delivery efficiency and safety.

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP4729507A1Rapidly-metabolized lipid compound

Publication Date: 2026.04.22 BEIJING JITAI PHARM TECH CO LTD

AI summary

Provided is a rapidly-metabolized lipid compound. The present invention relates in particular to a compound represented by formula (I), or a pharmaceutically acceptable salt, an isotopic variant, a tautomer or a stereoisomer thereof. Also provided are a nanoparticle pharmaceutical composition comprising the compound, and a use of the compound and a composition thereof in delivering nucleic acids.