OBJECTIVE: When synthetic particles are injected into a biofluid, proteins nonspecifically adsorb onto the particle surface and form a protein corona. Protein coronas are known to alter how particles function in blood; however, little is known about protein corona formation in synovial fluid or how these coronas change with osteoarthritis (OA). In this study, protein coronas were characterized on particles incubated within OA-affected or healthy rat knees. DESIGN: First, to evaluate particle collection techniques, magnetic polystyrene particles were placed in bovine synovial fluid and separated using either magnetics or centrifugation. In a second experiment, 12 male and 12 female Lewis rats received a simulated medial meniscal injury. At 2, 5, or 8 weeks post-surgery, operated and contralateral limbs were injected with clean magnetic particles ( = 8 per timepoint). After a 4-h incubation, animals were euthanized and particles were magnetically recovered. In both experiments, protein coronas were characterized using an Orbitrap fusion mass spectrometer. RESULTS: In the first experiment, the particle separation method affected the identified proteins, likely due to centrifugation forces causing some large proteins to spin-down with the particles. In the OA model, 300-500 proteins were identified in the particle-protein coronas with 35, 59, and 13 proteins differing between the OA-affected and contralateral limbs at 2, 5, and 8 weeks, respectively. In particular, plectin, a serine (or cysteine) proteinase inhibitor, and cathepsin B were more prominent in the particle-protein coronas of OA-affected knees. CONCLUSIONS: Synthetic particles nonspecifically adsorb proteins in synovial fluid, and these binding events differ with OA severity.