Journal of controlled release : official journal of the Controlled Release SocietyDec 14, 2016

Small self-clumping molecules that dissolve in acidic cell compartments as carriers for DNA, mRNA, siRNA, and exon-skipping therapies

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 2, 2026

Abstract

Polyethylenimine (PEI) modified to include aromatic domains enhances nucleic acid delivery efficiency, even for carriers as low as 1.8kDa.

Optimal DNA delivery activity is associated with PEIs having molecular weights between 10-30kDa.
PEIs below 1.8kDa show diminished activity, particularly with shorter nucleic acids like mRNA or siRNA.
Chemical modification of primary amines to aromatic domains maintains PEI's buffering abilities while enhancing pH-sensitive aggregation.
The salicylamide-grafted PEI demonstrates reliable in vitro transfection capabilities for mRNA, siRNA, and oligonucleotides.
In vivo testing reveals that intramuscular delivery of modified PEI leads to dystrophin-positive fibers in a mouse model of Duchenne muscular dystrophy without apparent toxicity.

Simplified

Efficiency of polyethylenimine (PEI) for nucleic acid delivery is affected by the size of the carrier and length of the nucleic acids. For instance, PEIs with molecular weights between 10-30kDa provide optimal DNA delivery activity whereas PEIs with molecular weights below 1.8kDa are ineffective. The activity of PEI is also severely diminished by substitution of DNA for shorter nucleic acids such as mRNA or siRNA. Here, through chemical modification of the primary amines to aromatic domains we achieved nucleic acid delivery by the 1.8kDa polyethylenimine (PEI) particles. This modification did not affect the PEI buffering abilities but enhanced its pH-sensitive aggregation, enabling stabilization of the polyplex outside the cell while still allowing nucleic acid release following cellular entry. The aromatic PEIs were then evaluated for their gene, mRNA, siRNA and 2'O-methyl phosphorothioate oligonucleotide in vitro transfection abilities. The salicylamide-grafted PEI showed to be a reliable carrier for delivering nucleic acids with cytoplasmic activity such as the mRNA and siRNA or nuclear diffusible oligonucleotide. It was then further equipped with polyethyleneglycol (PEG) and the delivery efficiency of the copolymer was tested in vivo for regeneration of dystrophin in the muscle of mdx mouse through a 2'O-methyl phosphorothioate-mediated splicing modulation. Intramuscular administration of polyplexes resulted in dystrophin-positive fibers in a mouse model of Duchenne muscular dystrophy without apparent toxicity. These findings indicate that precise modifications of low molecular weight PEI improve its bio-responsiveness and yield delivery vehicles for nucleic acids of various types in vitro and in vivo.

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Small self-clumping molecules that dissolve in acidic cell compartments as carriers for DNA, mRNA, siRNA, and exon-skipping therapies

Abstract

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