Redox-Responsive Polyplexes for Gene Delivery
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Solution Overview
Problem
Current gene delivery systems, such as those for DNA, mRNA, and CRISPR-Cas9, face challenges due to low cellular uptake efficiency, chemical degradation, and high cytotoxicity, particularly for large and complex structures like RNP and S1mplex, which hinder their clinical translation.
Innovation Solution
The development of cationic polymer-based nanovectors, specifically polyplexes formed by mixing negatively charged payloads with redox-responsive cationic copolymers like PBAP, which provide electrostatic interactions, endosomal escape capabilities, and stability, allowing for efficient delivery and release of genetic materials within cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naked DNA or mRNA is used for gene delivery, then the genetic material can reach the cell, but cellular uptake efficiency is low and the material is susceptible to chemical degradation
Solution Approach 1:
The patent uses cationic polymers as intermediary carriers to complex with negatively charged nucleic acids (DNA, mRNA), forming polyplexes that protect the genetic material from degradation while facilitating cellular uptake. The polymer acts as a mediator between the naked nucleic acid and the cellular environment, solving both the degradation and low uptake efficiency problems simultaneously.
2Reliability
If RNP or S1mplex complexes are used for CRISPR-Cas9 delivery, then genome editing can be achieved, but delivery remains challenging due to large size, complex structure, and mixed charges
Solution Approach 1:
The patent employs composite polyplex structures formed by complexing cationic polymers with RNP or S1mplex complexes. This composite approach allows the delivery system to handle the large size, complex structure, and mixed charges of CRISPR components, enabling efficient delivery while maintaining the functional integrity of the genome editing machinery.
3Productivity
If cationic polymers are used to enhance cellular uptake, then transfection efficiency improves, but cytotoxicity increases
Solution Approach 1:
The patent utilizes the pH parameter change between endosomal and cytosolic environments to trigger disassembly of the polyplex. The cationic polymer remains stable at endosomal pH but undergoes conformational changes or disassembles at cytosolic pH, releasing the genetic material with reduced cytotoxicity while maintaining high transfection efficiency through the initial endosomal escape.
4Stability of the object's composition
If polyplexes are formed to protect genetic material, then stability in vivo improves, but the system must efficiently release the payload inside cells
Solution Approach 1:
The patent designs dynamic polyplexes that adapt their stability based on the cellular environment. The cationic polymer forms stable complexes with nucleic acids in the extracellular environment and bloodstream, but undergoes dynamic changes upon entering the cell (pH change, enzymatic degradation, or redox conditions) to release the payload efficiently at the target site.
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
These polyplexes exhibit high transfection and genome editing efficiencies, protect genetic materials from degradation, have low cytotoxicity, and are stable in vivo, enabling effective delivery of DNA, mRNA, and protein-nucleic acid complexes to the appropriate subcellular locations.
Implementation Method 1
The polymers are redox-responsive copolymers containing disulfide bonds which can deliver proteins, nucleic acids and complexes of proteins and nucleic acids to cells
Implementation Method 2
The polymers are redox-responsive copolymers containing disulfide bonds which can deliver proteins, nucleic acids and complexes of proteins and nucleic acids to cells
Data Source
AI summary
Provided herein are nanoplexes comprising a payload selected from a protein and/or a polynucleic acid; and a plurality of copolymers comprising a first copolymer that is poly(N,N′-bis(acryloyl)cystamine-poly(aminoalkyl)) (PBAP), a second copolymer that is poly(C2-3 akylene glycol)-PBAP-poly(C2-3 akylene glycol), and a third copolymer that is TG-poly(C2-3 akylene glycol)-PBAP-poly(C2-3 akylene glycol)-TG wherein TG at each occurrence is independently a targeting ligand, a cell penetrating peptide, an imaging agent or a capping group, provided that a plurality of TG groups is a targeting ligand; wherein the payload is non-covalently complexed to one or more of the copolymers, one or more of the first, second, and/or third copolymers comprises an endosomal escape group having a pKa of about 4.5 to about 6.5, and optionally one or more of the first, second, and/or third copolymers comprises a host and a guest non-covalent crosslinker.