Scleroderma (systemic sclerosis, SSc) is a potentially devastating multisystem autoimmune disease clinically manifesting as fibrosis of skin and internal organs. The prevalence of SSc has been reported at 242 per million and the incidence at 19.3 new cases per million per year. There are limited disease modifying therapeutic options, resulting in high morbidity and mortality as well as substantial economic impact to society. Pathologically, SSc is characterized by excessive production and deposition of collagen. Like wound healing, and activation states of myofibroblasts, the effector scar-forming cells in fibrosis, are observed in SSc. Due to lack of adequate understanding of cause and pathology of scleroderma both diagnosis and treatment complicated. The initiation of organ fibrosis in scleroderma can result from aberrant wound-healing responses to autoimmune tissue injury, leading to activation of the effector scar-forming cells in fibrosis, the myofibroblasts. Failure of myofibroblasts to undergo apoptosis distinguishes non-resolving pathological fibrosis from self-limited physiological wound healing. Thus, therapeutic strategies selectively inducing myofibroblast apoptosis could not only halt or slow the progression of scleroderma fibrosis but also potentially reverse established fibrosis. In this project, we propose to develop novel drug delivery system to take this promising therapeutic strategy one step forward on the path to the clinic. In this proposal, we hypothesize that the development of nanomaterials for specific delivery of BCL-2 inhibitors to dermal myofibroblasts and prevent direct interaction with platelets, will increase the efficacy, specificity, and safety of the molecules for the treatment of scleroderma fibrosis. This novel strategy is appealing with multiple advantages: limited on-target thrombocytopenia, reduced toxicity, controlled release and increased efficacy and selectivity over free drug form. The long-term goal of this proposal is to utilize a cell specific delivery approach of highly patents and promising, BCL-2 inhibitors specifically to the myofibroblasts and test their ability to treat fibrosis.