Statement of Purpose: Advances in surgical techniques and immunology have enabled transplantation of composite tissue allografts (CTAs; e.g., upper extremity, face, genitourinary tissues) to treat complex soft tissue injuries and extremity amputations. However, >85% of transplant recipients develop at least one episode of rejection within the first year, and >50% experience multiple such episodes. Systemic distribution of orally or intravenously delivered immunosuppressants, such as tacrolimus, increases the likelihood of widespread side effects and is further dependent on patient compliance. To address these limitations, we have developed a nanosphere-based local drug delivery system using a biodegradable and bioresorbable tyrosine-derived nanospheres (TyroSpheres)  loaded in a water-soluble thin film. These films are designed to be implanted over the graft interface where they will rapidly dissolve, delivering tacrolimus-loaded TyroSpheres to the surrounding tissue and providing long-term, localized immunosuppression to reduce the incidence of rejection episodes.