Physiochemical Effects of Nanoparticles on Cell Nuclear Complex Pore Transport: A Coarse-Grained Computational Model

LY Zhang and MD Becton and N Liu and RD Averett and RM Pidaparti and XQ Wang, JOURNAL OF CHEMICAL THEORY AND COMPUTATION, 15, 6382-6392 (2019).

DOI: 10.1021/acs.jctc.9b00335

Understanding and controlling the interaction between nanoparticles and cell nuclei is critical to the development of the biomedical applications such as gene delivery, cellular imaging, and tumor therapy. Recent years have witnessed growing evidence that the size, shape, and the grafting density of the karyopherins ligands of nanoparticles provide a significant influence on the uptake mechanism of nanoparticles into cells; however, there is a lack of investigation into how these physical factors play a role in cellular nuclear uptake and how the nanoparticle enters the nucleus. Here, we build a computational framework to parametrically evaluate the effects of the size, shape, and the grafting density of the karyopherins ligands of designed nanoparticles on their transport through the nuclear pore complex of a cell nucleus so as to provide a novel scheme for nanoparticle design and precise nucleus-targeted therapy. Simulation results indicate that smaller spherical nanoparticles need to overcome a lower energy barrier than larger ones and also that nanoparticles with large grafting density exhibited greatly altered dynamics during the active transport process. Moreover, we observed that the shape and morphology of nanoparticles unambiguously determined their nuclear uptake pathways. Nuclear uptake is determined by an intricate interplay between physicochemical particle properties and nucleus properties. Our work provides a systematic understanding for nuclear uptake of nanoparticles, viruses, and bacteria and opens up a controllable design strategy for manipulating nanoparticle-nucleus interaction, with numerous applications in medicine, bioimaging, and biosensing.

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