Porous silicon (PSi) has been demonstrated as a promising drug delivery vector for poorly water-soluble drugs. Here, a simple and efficient method based on copper-free click chemistry was used to introduce targeting moieties to PSi nanoparticles in order to enhance the intracellular uptake and tumor specific targeting hydrophobic drug delivery. Two RGD derivatives (RGDS and iRGD) with azide-terminated groups were conjugated to bicyclononyne-functionalized PSi nanoparticles via copper-free azide-alkyne cycloaddition. The surface functionalization was performed in aqueous solution at 37 degrees C for 30 min resulting in conjugation efficiencies of 15.2 and 3.4% (molar ratios) and the nanoparticle size increased from 165.6 nm to 179.6 and 188.8 nm for RGDS and iRGD, respectively. The peptides modification enhanced the cell uptake efficiency of PSi nanoparticles in EA.hy926 cells. PSi-RGDS and PSi-iRGD nanoparticles loaded with sorafenib showed a similar trend for the in vitro antiproliferation activity compared to sorafenib dissolved in dimethyl sulfoxide. Furthermore, sorafenib-loaded PSi-RGDS deliver the drug intracellulary efficiently due to the higher surface conjugation ratio, resulting in enhanced in vitro antiproliferation effect. Our results highlight the surface functionalization methodology for PSi nanoparticles applied here as a universal method to introduce functional moieties onto the surface of PSi nanoparticles and demonstrate their potential active targeting properties for anticancer drug delivery. (C) 2013 Elsevier Ltd. All rights reserved