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Synthetic polymers are ubiquitous in the development of drug and polynucleotide delivery vehicles, offering promise for personalized medicine. However, the polymer structure plays a central yet elusive role in dictating the efficacy, safety, mechanisms, and kinetics of therapeutic transport in a spatial and temporal manner. Here, we decipher the intracellular pathways pertaining to shape, size, location, and mechanism of four structurally divergent polymer vehicles (Tr455, Tr477, jetPEI, and Glycofect) that create colloidal nanoparticles (polyplexes) when complexed with fluorescently labeled plasmid DNA (pDNA). Multiple high resolution tomographic images of whole HeLa (human cervical adenocarcinoma) cells were captured via confocal microscopy at 4, 8, 12, and 24 h. The images were reconstructed to visualize and quantify trends in situ in a four-dimensional spatiotemporal manner. The data revealed heretofore-unseen images of polyplexes in situ and structure-function relationships, i.e., Glycofect polyplexes are trafficked as the smallest polyplex complexes and Tr455 polyplexes have expedited translocation to the perinuclear region. Also, all of the polyplex types appeared to be preferentially internalized and trafficked via early endosomes affiliated with caveolae, a Rab-5-dependent pathway, actin, and microtubules.

Spatiotemporal Cellular Imaging of Polymer–pDNA Nanocomplexes Affords in Situ Morphology and Trafficking Trends