With an attempt to solubilize plasmid DNA (pDNA) in organic solvents, we developed nanocomplexation strategy by using block copolymer of polyethylene glycol-b-poly(L-lysine) (PEG-b-PLL). Self-assembly of PEG-b-PLL and pDNA in aqueous solution led to spherical nanocomplexes with core-shell structure when the +/- charge ratio (N/P) was higher than 1:1. This complexation had no significant impact on the helical structure of pDNA. After lyophilization, PEG-b-PLL/pDNA nanocomplexes originally formed in aqueous solution could be well dispersed in organic solvents such as THF and dichloromethane. Facilitating by nanocomplexation, pDNA could be encapsulated into PLGA nanoparticles with high efficiency, via oil-in-water emulsion solvent evaporation method. This complexation mediated pDNA solubilization in organic solvents may facilitate the development of novel nano- and micro-platforms for gene delivery. (C) 2012 Elsevier Inc. All rights reserved.