Macrophages are key orchestrators of inflammation as they secrete proteases and inflammatory cytokines. To date, therapies aimed at modulating macrophage phenotype have failed due to the short half-life of biomolecules in the body. Therefore, inhibition of inflammation by gene therapy constitutes a new hope.In the present study, we have assessed collagen hollow spheres as a reservoir system for polyplexes in order to transfect human macrophages while preserving cell viability. Polyplexes were formed by complexing G-Luc plasmid with a poly(2-dimethylaminoethyl methacrylate) poly(ethylene glycol) based hyperbranched polymer. Several ratios of polymer/pDNA (5:1, 8:1, 10:1 w/w) complexes in two different sphere sizes (1.24 and 4.5 mu m) were tested. Collagen hollow spheres were loaded with polyplexes up to 80 mu g of pDNA per mg of microspheres. The release of polyplexes from the spheres was delayed and prolonged i.e. 20% of the initial amount released in 5 days. Following incubation with polyplex-loaded microspheres, macrophages were transfected (polyplex pDNA:polymer ratio 1:10 w/w). In addition, collagen hollow spheres maintained cell viability as more than 80% of cells were viable after 4 days in culture. In contrast, when used alone, polyplexes were seen to be toxic, while there was no transfection detected. Taken together, these results show that collagen hollow spheres may be used as a reservoir for controlled gene delivery to macrophages. Unlike existing gene delivery systems, this system allows for macrophage transfection with minimal toxicity. Hence, this system has a potential for the delivery of a therapeutic gene in order to modulate inflammation. (C) 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.