The purpose of this study was to assess whether an alternative treatment approach that targets angiogenesis, delivered through ligand-targeted nanotherapy, would ameliorate inflammatory arthritis. Arthritis was induced using the K/BxN mouse model of inflammatory arthritis. After arthritis was clearly established, mice received three consecutive daily doses of _v3-targeted fumagillin nanoparticles. Control groups received no treatment or _v3-targeted nanoparticles without drugs. Disease score and paw thickness were measured daily. Mice that received _v3-targeted fumagillin nanoparticles showed a significantly lower disease activity score (mean score of 1.4±0.4; P<0.001) and change in ankle thickness (mean increase of 0.17±0.05 mm; P<0.001) 7 d after arthritis induction, whereas the group that received _v3-targeted nanoparticles without drugs exhibited a mean arthritic score of 9.0 ± 0.3 and mean change in ankle thickness of 1.01 ± 0.09 mm. Meanwhile, the group that received no treatment showed a mean arthritic score of 9.8 ± 0.5 and mean change in ankle thickness of 1.05 ± 0.10 mm. Synovial tissues from animals treated with targeted fumagillin nanoparticles also showed significant decrease in inflammation and angiogenesis and preserved proteoglycan integrity. Ligand-targeted nanotherapy to deliver antiangiogenic agents may represent an effective way to treat inflammatory arthritis.—Zhou, H.-F., Chan, H. W., Wickline, S. A., Lanza, G. M., Pham, C. T. N. _v3-Targeted nanotherapy suppresses inflammatory arthritis in mice.