Structural changes occurring on a millisecond time scale during uptake of DNA by cationic lipid nanocarriers are monitored by time-resolved small-angle X-ray scattering (SAXS) coupled to a rapid-mixing stopped-flow technique. Nanoparticles (NPs) of nanochannel organization are formed by PEGylation, hydration, and dispersion of a lipid film of the fusogenic lipid monoolein in a mixture with positively charged (DOMA) and PEGylated (DOPE-PEG2000) amphiphiles and are characterized by the inner cubic structure of very large nanochannels favorable for DNA upload. Ultrafast structural dynamics of complexation and assembly of these cubosome particles with neurotrophic plasmid DNA (pDNA) is revealed thanks to the high brightness of the employed synchrotron X-ray beam. The rate constant of the pDNA/lipid NP complexation is estimated from dynamic roentgenograms recorded at 4 ms time resolution. pDNA upload into the vastly hydrated channels of the cubosome carriers leads to a fast nanoparticle-nanoparticle structural transition and lipoplex formation involving tightly packed pDNA.

§European Synchrotron Radiation Facility 6 rue Jules Horowitz F 38043 Grenoble France

†Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic CZ 16206 Prague Czech Republic

‡CNRS UMR8612 Institut Galien Paris Sud Univ Paris Sud 11 F 92296 Châtenay Malabry France

⊥Laboratory for Soft Matter Electron Microscopy Bayreuth Institute of Macromolecular Research University of Bayreuth D 95440 Bayreuth Germany

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