Background of PEI Transfection Reagents
About 50 years ago, Theodore Friedmann and Richard Roblin proposed using “good” exogenous DNA to replace “defective” DNA to cure human genetic diseases—the earliest idea of gene therapy. Naked DNA is easily degraded by nucleases, so researchers have spent decades developing safe, efficient delivery vectors. Viral vectors showed high transfection efficiency but suffer from severe immune responses, limited cargo size, and high cost. Consequently, non-viral vectors emerged, including organic carriers like cationic polymers, liposomes, dendrimers, and micelles, and inorganic carriers like metals and quantum dots. These carriers are easy to synthesize, have low immunogenicity, and package nucleic acids efficiently. PEI was developed in this context and has been widely applied in nucleic acid transfection.
Figure 1. Polymeric vectors used for nucleic acid delivery
Relationship Between PEI Structure and Transfection
PEI (polyethylenimine) exists as linear PEI (lPEI) and branched PEI (bPEI), depending on synthesis. At the same molecular weight, bPEI compresses nucleic acids more effectively, but lPEI has lower toxicity and higher in vivo efficiency. Free PEI chain length also affects transfection: longer free chains improve efficiency but increase cytotoxicity. Transfection efficiency positively correlates with PEI molecular weight, while toxicity is inversely correlated.
Figure 2. Structures of linear and branched PEI
Mechanism of PEI Transfection
PEI is considered the “gold standard” for delivering pDNA, miRNA, and siRNA. It compresses negatively charged nucleic acids into cationic complexes that bind to negatively charged cell surface proteoglycans and enter cells via endocytosis. After uptake into early endosomes, escape into the cytosol or nucleus is required. Two mechanisms facilitate this:
- Membrane perforation—PEI interacts with anionic endosomal lipids to form pores.
- Osmotic swelling/rupture—unprotonated amines in PEI act as a proton sponge, causing proton influx and endosomal swelling that leads to rupture.
Figure 3. In vivo delivery of nucleic acids
RNA is released into the cytoplasm to act biologically, while DNA travels to the nucleus via nuclear pores. Because PEI complexes can nonspecifically interact with serum proteins, it is recommended to prepare the complexes in serum-free conditions.
References:
Cuiping Jiang, Jiatong Chen, Zhuoting Li, Zitong Wang, Wenli Zhang & Jianping Liu (2019): Recent advances in the development of polyethylenimine-based gene vectors for safe and efficient gene delivery, Expert Opinion on Drug Delivery, DOI: 10.1080/17425247.2019.1604681
Alexandra S. PiotrowskiDaspit, Amy C. Kauffman, Laura G. Bracaglia, et al. Polymeric Vehicles for Nucleic Acid Delivery [J]. Adv Drug Deliv Rev. 2020;156:119–132. doi:10.1016/j.addr.2020.06.014
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