Current Designs of Polymeric Platforms Towards the Delivery of Nucleic Acids Inside the Cells with Focus on Polyethylenimine

Abstract

Background: Gene delivery is a promising technology for treating diseases linked to abnormal gene expression. Since nucleic acids are the therapeutic entities in such approach, a transfecting vector is required because the macromolecules are not able to efficiently enter the cells by themselves. Viral vectors have been evidenced to be highly effective in this context; however, they suffer from fundamental drawbacks, such as the ability to stimulate immune responses. The development of synthetic vectors has accordingly emerged as an alternative. Objectives: Gene delivery by using non-viral vectors is a multi-step process that poses many challenges, either regarding the extracellular or intracellular media. We explore the delivery pathway and afterwards, we review the main classes of non-viral gene delivery vectors. We further focus on the progresses concerning polyethylenimine-based polymer-nucleic acid polyplexes, which have emerged as one of the most efficient systems for delivering genetic material inside the cells. Discussion: The complexity of the whole transfection pathway, along with a lack of fundamental understanding, particularly regarding the intracellular trafficking of nucleic acids complexed to non-viral vectors, probably justifies the current (beginning of 2021) limited number of formulations that have progressed to clinical trials. Truly, successful medical developments still require a lot of basic research. Conclusion: Advances in macromolecular chemistry and high-resolution imaging techniques will be useful to understand fundamental aspects towards further optimizations and future applications. More investigations concerning the dynamics, thermodynamics and structural parameters of polyplexes would be valuable since they can be connected to the different levels of transfection efficiency hitherto evidenced.

A Nanoparticle RIG-I Agonist for Cancer Immunotherapy

“…17,40 However, recent clinical trials, 25 and most preclinical studies to date 11,13,23,24 , have employed the cationic polymeric transfection reagent JetPEI TM , which electrostatically condenses nucleic acids and facilities their release from the endolysosome. 41 While PEI-based approaches remain promising, and merit continued development, their clinical translation has been hindered by toxicity concerns, a proclivity for accumulation in the lungs, and a relatively low efficiency for cytosolic delivery via the still debated "proton sponge" mechanism. 42,43 By contrast, LNPs have rapidly emerged as one of the most versatile platforms for delivery of a diverse array of nucleic acids, and are essential to the efficacy of several recently approved nucleic acid therapeutics.…”

Degradable Cationic Polycarbamates Designed for Robust IL-12 Gene Therapy against Metastatic Lung Cancer

“…The Michael-type addition and Schiff's base reaction were frequently adopted to yield different BPEIs cross-linked by acid-labile (or reducible) cross-linkers. 16 As a result, these BPEI derivatives were degradable in acidified endosomes or a reductive cytoplasm. Nevertheless, these convenient conjugation reactions are often ineffective in giving a degradable LPEI comprising multiple secondary amino groups.…”

Balancing gene transfection and cytotoxicity of nucleic acid carriers with focus on ocular and hepatic disorders: evaluation of hydrophobic and hydrophilic polyethyleneimine derivatives

“…[7][8][9] These concerns motivated the search for non-viral gene carriers and those based on polymeric materials emerged as potential candidates since the preparation is fairly simple, they are rather stable and can be designed to be relatively safe. [10][11][12][13] Polycation polyethylenimine (PEI) is one of the most extensively researched polymeric gene vectors. 14 However, its transfection efficiency still does not compete with that of viral vectors, 15 and it also exhibits significant cytotoxicity due to its membrane disruptive properties, 16,17 thus optimizations and improved derivatives are required.…”