Non-viral gene delivery using polyethylenimine (PEI) has shown tremendous promise as a therapeutic technique. Through the formation of nanoparticles (NPs), PEIs protect genetic material such as DNA from degradation. Escape of the NPs from endosomes and lysosomes is facilitated by PEI's buffering capacity over a wide range of pH. However, little is known about the effects of endosomal acidification on the morphology of the NPs. In this work, large-scale coarse-grained simulations performed to mimic endosomal acidification reveal that NPs undergo a resizing process that is highly dependent on the N/P ratio (ratio of PEI nitrogen to DNA phosphate) at which they are prepared. With a low N/P ratio, NPs further aggregate after endosomal acidification, whereas with a high N/P ratio they dissociate. The mechanisms behind such NP resizing and its consequences on endosomal escape and nuclear trafficking are discussed. Based on the findings, suggestions are made on the PEI architecture that may enhance NP dissociation driven by endosomal acidification.
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