Bioreducible Zinc(II)-Coordinative Polyethylenimine with Low Molecular Weight for Robust Gene Delivery of Primary and Stem Cells

Abstract

To transform common low-molecular-weight (LMW) cationic polymers, such as polyethylenimine (PEI), to highly efficient gene vectors would be of great significance but remains challenging. Because LMW cationic polymers perform far less efficiently than their high-molecular-weight counterparts, mainly due to weaker nucleic acid encapsulation, herein we report the design and synthesis of a dipicolylamine-based disulfide-containing zinc(II) coordinative module (Zn-DDAC), which is used to functionalize LMW PEI (M ≈ 1800 Da) to give a non-viral vector (Zn-PD) with high efficiency and safety in primary and stem cells. Given its high phosphate binding affinity, Zn-DDAC can significantly promote the DNA packaging functionality of PEI and improve the cellular uptake of formulated polyplexes, which is particularly critical for hard-to-transfect cell types. Furthermore, Zn-PD polymer can be cleaved by glutathione in cytoplasm to facilitate DNA release post internalization and diminish the cytotoxicity. Consequently, the optimal Zn-PD mediates 1-2 orders of magnitude higher gluciferase activity than commercial transfection reagents, Xfect and PEI, across diverse cell types, including primary and stem cells. Our findings provide a valuable insight into the exploitation of LMW cationic polymers for gene delivery and demonstrate great promise for the development of next-generation non-viral vectors for clinically viable gene therapy.

Polyethylenimine-based nanocarriers in co-delivery of drug and gene: a developing horizon

“…Tissue engineering [48–51], gene therapy [52,53], cancer treatment [54,55], chemotherapy [56,57] and medical applications [58–60] are the applications of PEI.…”

Enhancing the antivirus activity of chimeric canine interferon with ricin subunit B by using nanoparticle formulations

“…Despite the main applications of PEI polymer as a gene vector for medical applications, [36][37][38][39][40] our study assembled the recombinant protein and PEI to enhance the antiviral activity of rCaIFNa/RTB. The rCaIFNa/RTB@PEI 10000 NPs were synthesized by mixing rCaIFNa/RTB and PEI 10000 in a water solution, followed by centrifugation and washing.…”

Virus‐inspired and mimetic designs in non‐viral gene delivery

“…In addition to evolution of cationics (e.g. transforming the cationic headgroup and length of the hydrophobic chains), other strategies have been applied in recent years, such as zinc (Zn)‐coordinative and fluorinated modification . Liu et al .…”

“…transforming the cationic headgroup and length of the hydrophobic chains), other strategies have been applied in recent years, such as zinc (Zn)‐coordinative and fluorinated modification . Liu et al . developed diverse gene delivery carriers based on a Zn coordinated strategy, showing notable benefits in tight DNA condensation, robust cellular uptake, efficacious endosomal destabilization and high transfection efficacy.…”