Surface-Conjugated PACE Nanoparticles for Stable, Targeted mRNA Delivery

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current non-viral vectors for gene delivery, such as cationic lipids and polymers, face issues with instability in physiological fluids, aggregation, and high toxicity, limiting their clinical applicability and efficiency, particularly for systemic delivery of nucleic acids like mRNA.

Innovation Solution

Development of biodegradable poly(amine-co-ester) nanoparticles modified with poly(ethylene glycol) (PACE-PEG) and optionally blended with a second PACE polymer, featuring surfactants like poly(vinyl alcohol sulfone) for non-covalent conjugation, to create a targeted and sustained release system for nucleic acids.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If cationic lipids or polymers are used for gene delivery, then transfection efficiency is improved, but toxicity increases and stability in physiological fluids deteriorates

Engineering Contradiction:

Improvetransfection efficiencyVSAvoidtoxicity

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the surface charge parameter from positive to negative by using anionic polymers. This fundamental parameter change allows the vector to maintain transfection efficiency while avoiding the toxicity associated with excess positive charges, as the negative charge does not cause the same harmful interactions with cellular components

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite material structures by combining anionic polymers with specific molecular architectures that include both charge-bearing and charge-neutral segments. This composite approach allows the vector to achieve stable complex formation with nucleic acids while the overall structure maintains reduced toxicity and improved stability in physiological fluids

Inventive Principle:

Principle #40Composite materials

2Stability of the object's composition

If excess positive charge is used to form stable polyplexes, then complex stability is improved, but aggregation in serum and clearance by RES increases

Engineering Contradiction:

Improvecomplex stabilityVSAvoidcirculatory stability

Core Design Contradiction:

Stability of the object's compositionVSReliability

Solution Approach 1:

The patent inverts the conventional approach by using anionic polymers instead of cationic ones. This inversion allows the formation of stable complexes through alternative mechanisms while avoiding the aggregation and rapid clearance problems that plague positively charged vectors in serum environments

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent changes the charge parameter from positive to negative, which fundamentally alters the interaction profile with serum components. This parameter change prevents the electrostatic attraction between positively charged polyplexes and negatively charged serum proteins that leads to aggregation and RES clearance

Inventive Principle:

Principle #35Parameter changes

3Productivity

If cationic vectors are used for gene delivery, then cellular uptake is enhanced, but immune response and inflammatory reactions increase

Engineering Contradiction:

Improvecellular uptakeVSAvoidimmune response

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent changes the surface charge parameter from positive to negative, which reduces the activation of immune cells and inflammatory pathways that are typically triggered by cationic vectors, while still maintaining effective cellular uptake through alternative mechanisms

Inventive Principle:

Principle #35Parameter changes

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 nanoparticles provide efficient, non-toxic, and targeted delivery of nucleic acids, including mRNA, with improved stability and reduced immune response, enhancing cellular uptake and minimizing systemic toxicity.

Implementation Method 1

Both cationic lipid and cationic polymer systems deliver genes by forming condensed complexes with negatively charged DNA through electrostatic interactions

Methodology Applied

Scientific EffectElectrostatic interactions: Electrostatics

Implementation Method 2

biodegradable poly(amine-co-ester) nanoparticles modified with poly(ethylene glycol) (PACE-PEG)

Methodology Applied

Scientific EffectSteric stabilization:

Implementation Method 3

featuring surfactants like poly(vinyl alcohol sulfone) for non-covalent conjugation

Methodology Applied

Scientific EffectSurfactant effect: Surfactant

Data Source

PatentUS20250241865A1Surface conjugation to poly(amine-co-ester) nanoparticles for targeting to cells and tissues

Publication Date: 2025.07.31 YALE UNIVERSITY

AI summary

Nanoparticles useful for drug delivery are described. In one aspect, the nanoparticles contain poly(amine-co-ester)s or poly(amine-co-amide)s (PACE) modified with poly(ethylene glycol) (PACE-PEG), and can be optionally blended with a second PACE polymer optionally containing endgroup modifications. In another aspect, the nanoparticles contain a core containing a PACE polymer optionally containing endgroup modifications, and a polymeric surfactant non-covalently conjugated to the surface of the nanoparticles. The nanoparticles contain a peptide or protein targeting moiety that is covalently conjugated to the PACE-PEG polymer or to the surfactant on the surface of the nanoparticles via a linkage that contains a succinimide or substituted sulfone moiety, respectively. The nanoparticles provide as a versatile platform for the delivery of nucleic acids, such as mRNA.