Chitosan (CS)-modified poly(D,L-lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) were prepared and their lung targetability after intravenous administration was elucidated. PLGA NPs (mean diameter: 225 nm; polydispersity index: 0.11; zeta potential: -15 mV), 0.2% (w/v) CS-coated PLGA NPs (CS02-PLGA NPs, mean diameter: 264 nm; polydispersity index: 0.17; zeta potential: -7 mV), and 0.5% (w/v) CS-coated PLGA NPs (CS05-PLGA NPs, mean diameter: 338 nm; polydispersity index: 0.23; zeta potential: 12 mV) were fabricated by a modified solvent evaporation method. PLGA NPs maintained their initial particle size in different media, such as human serum albumin (HSA) solution, rat plasma, and distilled water (DW), while CS05-PLGA NPs exhibited the formation of aggregates in early incubation time and disassembly of those into the NPs in late incubation time (at 24 h). According to the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, the binding affinity of CS05-PLGA NPs with HSA and rat plasma was higher than that of PLGA NPs. By a near-infrared fluorescence (NIRF) imaging test in the mouse, the selective accumulation of CS05-PLGA NPs, rather than PLGA NPs, in lung tissue was demonstrated. These findings suggest that CS05-PLGA NPs can form transient aggregates in the blood stream after intravenous administration and markedly improve lung targeting efficiency, compared with PLGA NPs. (C) 2016 Elsevier Inc. All rights reserved.