Project Summary Tendinopathy is a tendon disorder that is highly prevalent in the aged population. It is characterized by tendon deterioration that often leads to tendon rupture, and is associated with pain, swelling and impaired performance. There is currently no cure for tendinopathy and an urgent need for effective treatments for tendinopathy. The technology to be developed is microRNA (miR)-221-5p for the treatment of tendinopathy. Our preliminary studies identified that miR-221-5p exhibited a therapeutic effect in a rodent model of tendinopathy and may exert its therapeutic effect, at least in part, by suppressing expression of pro-inflammatory mediators that contribute to the pathogenesis of tendinopathy. This project will test the hypothesis that chemically modified miR-221-5p exerts an enhanced effect on mitigating tendinopathy. The Phase II study will focus on providing critical evidence towards developing miR-221-5p as an FDA-approved product for the treatment of tendinopathy. In Aim 1, we will determine the chemical formulation and treatment condition of miR-221-5p using a collagenase- induced model of tendinopathy. In Aim 2, we will determine the efficacy and safety of miR-221-5p on tendinopathy in rabbits. Successful completion of the proposed studies will identify miR-221-5p as a new drug for the treatment of tendinopathy and other chronic inflammatory diseases.