Highlights: Using proprietary exosome tethering modification technology, Treg-derived exosomes were engineered with a surface protein, cytotoxic T lymphocyte associated protein 4 (CTLA-4) to increase selective targeting to immune cells; this patented technology requires no genetic modifications, overcomes known limitations of exosome manipulation, and enables tethering of multiple potential proteins to an exosome surface and loading of therapeutic cargo in the exosome interior; CTLA-4-engineered Treg exosomes (CTLA-4-Treg exosomes) dramatically increased targeting of, binding to, internalization of, and uptake into immune cells including macrophages and T cells; this technology can serve as a platform to engineer the exosome surface with proteins of interest to target specific cell and tissue types to potentially treat epitope driven autoimmune diseases and cancer.