Nonviral nanoparticle vectors cannot yet become competitive over natural virus-based counterparts in many therapy strategies, which ties with their poor nanoparticle quality, slow and ineffective endocytosis-mediated cellular uptake, and undesired cytotoxicity. This may fall in the tolerance for general gene delivery applications, but definitely undesired in vaccine or reprogramming type of applications as high, quick transfection and high cell viability is essential to their success. We develop new AuNP-Polyplex Electroporation based new delivery route, in which (1) monodispersed gold nanoparticles (AuNPs) are used to provide controlled assembly domain and environment with precise management on molecule interactions to obtain homogeneous polyplex in size, structure, and component quantity; (2) AuNPs also help fix free and dissociated cationic polymer to reduce their cytotoxicity and enhance electroporation based delivery route; (3) electroporation is adopted to bypass the slow and inefficient endocytosis process and to promote direct cytosolic delivery and quick nuclear entry. In this hybrid approach, AuNPs of various sizes are first coated with polyethylenimine (PEI), which are further conjugated with DNA plasmids or siRNA molecules to form AuNPs-polyplex. The hybrid nanoparticlesare then mixed with cells for electroporation treatment. The delivery efficiency is evaluated with K562 cells, showing 1.5~2 folds improvement on the transfection efficiency and no significant increase of toxicity when compared to free plasmid delivery by electroporation alone. To help reveal the assembly and release dynamics, dissipative particle dynamics (DPD) simulation and coarse-grained models are coupled to reveal the encapsulation and release details of siRNA in different polymers/AuNPs systems. The computational results are further compared to the experimental observations. With wise control strategy on the assembly quality, we anticipate such combination of physical and chemical delivery concept may stimulate further exploration in the delivery of various therapeutic materials for both in vitro and in vivo applications in vaccine or reprogramming type of applications.

Gold nanoparticle-polyplex electroporation in the enhancement of nucletic acid delivery

256th National Meeting (2018)

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