To establish a homing signal in the lung to recruit circulating stem cells for tissue repair, we formulated a nanoparticle, SDF-1 alpha NP, by complexing SDF-1 alpha with dextran sulfate and chitosan. The data show that SDF-1 alpha was barely released from the nanoparticles over an extended period of time in vitro (3% in 7 days at 37 degrees C); however, incorporated SDF-1 alpha exhibited full chemotactic activity and receptor activation compared to its free form. The nanoparticles were not endocytosed after incubation with Jurkat cells. When aerosolized into the lungs of rats, SDF-1 alpha NP displayed a greater retention time compared to free SDF-1 alpha (64 vs 2% remaining at 16 h). In a rat model of monocrotaline-induced lung injury, SDF-1 alpha NP, but not free form SDF-1 alpha, was found to reduce pulmonary hypertension. These data suggest that the nanoparticle formulation protected SDF-1 alpha from rapid clearance in the lung and sustained its biological function in vivo.