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Gene-therapy Inspired Polycation Coating for Protection of DNA Origami Nanostructures

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Nucleophile responsive charge-reversing polycations for pDNA transfection.

Reece W Lewis¹, Aswin Muralidharan^1,2,3, Benjamin Klemm¹

¹Department of Chemical Engineering, Delft University of Technology 2629 HZ Delft The Netherlands R.W.Lewis@tudelft.nl R.Eelkema@tudelft.nl.

Polymer Chemistry

|April 10, 2023

Summary

New charge-reversing polycations improve gene therapy by releasing DNA inside cells. This novel approach enhances transfection efficiency and reduces toxicity compared to traditional polycationic carriers.

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Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA

Generation of Cationic Nanoliposomes for the Efficient Delivery of In Vitro Transcribed Messenger RNA

Published on: February 1, 2019

Area of Science:

Biomaterials Science
Gene Therapy
Nanotechnology

Background:

Polycationic carriers are promising for gene therapy due to low cost and scalability.
Inefficient intracellular unpacking of genetic material limits transfection efficiency.
Charge-reversing polycations offer controlled intracellular DNA release.

Purpose of the Study:

To develop and characterize a novel class of charge-reversing polycations.
To investigate the mechanism of charge reversal via reaction with cellular nucleophiles.
To evaluate the performance of these polycations in a lipopolyplex formulation for gene delivery.

Main Methods:

Synthesis of a new class of charge-reversing polycations.
Investigating the kinetics of deionization with primary amines and thiols.
Formulating lipopolyplexes with the novel polycations.
Assessing transfection efficiency and cytotoxicity in mammalian cells.

Main Results:

The polycations undergo a cationic-to-neutral charge conversion triggered by cellular nucleophiles, with faster reaction kinetics for thiols.
The charge-reversal mechanism allows for slow deionization extracellularly and rapid deionization intracellularly.
Lipopolyplexes formulated with these charge-reversing polycations demonstrated improved transfection efficiency.
Reduced cytotoxicity was observed compared to non-responsive polycationic controls.

Conclusions:

Charge-reversing polycations offer a viable strategy to overcome intracellular unpacking limitations in gene therapy.
The tunable deionization kinetics enable targeted cargo release within the cellular environment.
This approach holds potential for developing safer and more effective gene delivery systems.