The objective of this study was to develop polymeric nanospheres (NPs) that are able to selectively target the activated vascular endothelium and to deliver co-encapsulated anti-angiogenic agents for improved treatment efficacy in inflammatory diseases with an angiogenic component. We evaluated a novel poly(d,l)-lactide (PLA)-based polymer, grafted with a synthetic ligand specific for selectin (PLA-g-SEL), for the preparation of functionalized NPs. The NPs were produced according to a double emulsion-solvent diffusion/evaporation method, allowing the co-encapsulation of hydrophilic and lipophilic drugs. Incorporation of the functionalized polymer enhanced the internalization of fluorescein-labeled NPs by lipopolysaccharide-activated vascular endothelial cells relative to control NPs, as evidenced by confocal laser scanning microscopy and quantitative fluorescence measurements. Two anti-angiogenic agents, endostatin and paclitaxel, were co-loaded in the functionalized NPs. Respective drug loadings were optimized by adjusting polymer composition, as well as by the microemulsion technique. NPs loaded with either of the chosen drugs or with a combination of them were tested for their anti-angiogenic efficacy in human umbilical vascular endothelial cell (HUVEC) culture in vitro and rat aorta tissue culture ex vivo models. An enhanced anti-proliferative effect on HUVECs and heightened anti-angiogenic action on rat aorta ring cultures was observed for the loaded drugs compared to the free molecules. Moreover, combined loaded treatments were found to be more potent, evoking additive and even synergetic outcomes (at lower doses) greater than the corresponding single-loaded treatments in inhibiting new vessels sprouting in rat aortic rings.