Transient Destabilization of Biological Membranes Contributes to the Superior Performance of Star-Shaped PDMAEMA in Delivering pDNA

[Image: see text] Nonviral DNA vectors are promising alternatives to viral ones. Their use in DNA medicine is limited by an inability to transfect, for example, nondividing or suspension cells. In recent years, star-shaped synthetic polycationic vectors, so called “Nanostars”, have shown some promise in this regard, at least when compared to the “gold standard” in nonviral vectors, namely, linear poly(ethyleneimine) (l-PEI). It has been hypothesized that an ability to transiently destabilize cellular membranes is partially responsible for the phenomenon. This hypothesis is investigated here, taking human leukemia suspension cells (Jurkat cells) as an example. Contrary to l-PEI, the Nanostars promote the cellular uptake of small, normally membrane-impermeant molecules (trypan blue and propidium iodide) as well as that of fluorescent polystyrene beads (average diameter 100 nm). Since Nanostars, but not l-PEI, are apparently able to deliver DNA to nuclei of nondividing cells, nuclear uptake is, in addition, investigated with isolated cell nuclei. Our results provide evidence that Nanostars are more efficient than l-PEI in increasing the nuclear membrane association/permeability, allowing accumulation of their cargo on/in the nucleus.