Osteoarthritis (OA) is a degenerative joint disease that affects over 32 million individuals in the United States, causing debilitating joint destruction and chronic joint pain, stiffness, and physical impairment. To restore and improve the patient’s quality of life, total knee arthroplasty (TKA) is the most common surgical intervention performed for OA to replace the compromised joint with artificial femoral and tibial implants. Despite continued advancements in TKA procedures and implants, many post-operative complications still arise. Nonetheless, the demand for TKA and subsequent revisions is projected to grow exponentially to 3.48 million patients by 2030 with annual healthcare and patient costs to exceed $1.1 billion. While TKA has beneficial impacts on patients, the most critical complications of TKA are infection, inflammation, and arthrofibrosis. Treatments for infection exists, but these are usually involved and difficult; to our knowledge, there are no available interventions for arthrofibrosis beyond repeat surgery or physiotherapy. Furthermore, clinical studies have not paid sufficient attention to postoperative treatments of inflammation. Thus, while individual therapies may exist for each complication, there is a significant clinical need for a multi-targeted approach to prevent the development of these complications. In this Phase I SBIR, we propose to develop and evaluate a multifunctional, nitric oxide (NO) and antibiotic- loaded liposomes (ABLipo) releasing BionanomatrixTM coating on cobalt-chromium (CoCr) knee implants. In vitro, the implant coating will be optimized and characterized for release kinetics, coating uniformity/stability, and ability to prevent or mitigate infection/biofilm formation, inflammation, and fibrotic tissue formation. In vivo, we will evaluate the efficacy of the coated implants in a rabbit TKA infection model. Development of the BionanomatrixTM and ABLipo coating platform will target the critical complications of TKA as described above. If successful, this approach and findings will be readily translated to other orthopedic implants beyond knee implants. After successful completion of this Phase I SBIR proposal, we plan to further this research to a Phase II SBIR study with a larger-scale animal study, microbiological mechanism assessments, and ASTM/ISO standardized biocompatibility studies for future FDA applications.