To improve design processes in the field of nanomedicine, in vitro characterization of nanoparticles with systematically varied properties is of great importance. In this study, surface sensitive analytical techniques were used to evaluate the responsiveness of nano-sized drug-loaded polyelectrolyte complexes when adsorbed to model lipid membranes. Two bioreducible poly(amidoamine)s (PAAs) containing multiple disulfide linkages in the polymer backbone (SS-PAAs) were synthesized and used to form three types of nanocomplexes by self-assembly with human insulin, used as a negatively charged model protein at neutral pH. The resulting nanoparticles collapsed on top of negatively charged model membranes upon adsorption, without disrupting the membrane integrity. These structural rearrangements may occur at a cell surface which would prevent uptake of intact nanoparticles. By the addition of glutathione, the disulfide linkages in the polymer backbone of the SS-PAAs were reduced, resulting in fragmentation of the polymer and dissociation of the adsorbed nanoparticles from the membrane. A decrease in ambient pH also resulted in destabilization of the nanoparticles and desorption from the membrane. These mimics of intracellular environments suggest dissociation of the drug formulation, a process that releases the protein drug load, when the nanocomplexes reaches the interior of a cell. (C) 2011 Elsevier Inc. All rights reserved.