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Combinatorial library of biodegradable polyesters enables delivery of plasmid DNA to polarized human RPE monolayers for retinal gene therapy

Efficient gene delivery into hard-to-transfect cells is still a challenge despite significant progress in the development of various gene delivery tools. Non-viral and synthetic polymeric nanoparticles offer an array of advantages for gene delivery over the viral vectors and high in demand as they are safe to use, easy to synthesize and highly cell-type specific. Here we demonstrate the use of a high-throughput screening (HTS) platform to screen for biodegradable polymeric nanoparticles (NPs) that can transfect human retinal pigment epithelial (RPE) cells with high efficiency and low toxicity. These NPs can deliver plasmid DNA (pDNA) to RPE monolayers more efficiently compared to the commercially available transfection reagents without interfering the global gene expression profile of RPE cells. In this work, we have established an HTS platform and identified synthetic polymers that can be used for high efficacy non-viral gene delivery to human RPE monolayers, enabling gene loss- and gain-of-function studies of cell signaling and developmental pathways. This platform can be used to identify the optimum polymer, weight-to-weight ratio of polymer to DNA, and the dose of NP for various retinal cell types.