Native quantum dots (QDs) made up of semiconductor nanocrystals (NCs) are toxic in nature but due to their excellent optical properties, they have proven themselves to be an attractive choice in biological labeling and targeting. In order to improve the general biocompatibility of lead sulfide (PbS) NCs, we present a new and simple procedure for preparing PbS/gelatin core-shell nanoparticles cross-linked with glutaraldehyde (GA) molecules. The phase composition, morphology, luminescence and in vitro photostability of the samples were characterized by X-ray diffraction (XRD). Fourier transform infrared (FTIR), transmission electron microscope (TEM) and fluorescence spectroscopy, respectively. The XRD analysis showed that the PbS NCs were of the cubic structure, the mean crystallite size was calculated to be 13.5 nm and the calculated lattice constant using Bragg's equation was 0.5950 nm, which was very close to its value in the standard card (JCPDS No. 5-592). In vitro test revealed that compared with bare PbS NCs, the photostability of the core-shell nanostructure remarkably improved. In addition, possible formation mechanisms of the PbS/gelatin nanoparticles were discussed in detail. Consequently, the advantages of high stability as well as high fluorescent intensity and biocompatibility make the core-shell nanoparticles promising candidates for in vivo biological targeting applications. (C) Elsevier Inc. All rights reserved.