Bioreducible Zinc(II) Coordinative PEI with Low Molecular Weight for Robust Gene Delivery of Primary and Stem cells.

To transform the common low molecular weight (LMW) cationic polymers, such as polyethylenimine (PEI) to highly efficient gene vectors will be of great significance but remains challenging. Since that LMW cationic polymers perform far less efficient to their high molecular weight counterparts mainly due to weaker nucleic acid encapsulation, herein, we report the design and synthesis of a dipicolylamine (DPA)-based disulfide-containing zinc(II) coordinative module (Zn-DDAC), which is used to functionalize LMW PEI (Mw~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 PEI1.8k 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 PEI25k across diverse cell types, including primary and stem cells. Our findings provide a valuable insight to exploit LMW cationic polymers for gene delivery and demonstrate great promise to develop non-viral vectors of next generation for clinically viable gene therapy.