TRAIL Coated Genetically Engineered Immunotherapeutic Nano‐Ghosts Vesicles Target Human Melanoma‐Avoiding the Need for High Effective Therapeutic Concentration of TRAIL

Abstract Cancer cell therapy using cytotoxic T lymphocytes (CTL) or mesenchymal stem cells (MSC) possesses hurdles due to the cells, susceptibility to host induced changes. Here, versatile inanimate broadly applicable nanovesicles, termed immunotherapeutic‐nano‐ghosts (iNGs), are armed with inherent surface‐associated targeting and therapeutic capabilities in which the promise and benefits of MSC therapy and T cell immunotherapy are combined into one powerful off‐the‐shelf approach for treating malignant diseases. To mimic the cytotoxic or immunosuppressive functions of T cells, iNG are produced from MSC that were genetically engineered (GE) or metabolically manipulated to express additional membrane‐bound proteins, endowing the NGs derived therefrom with additional surface‐associated functions such as tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL). iNGs from GE‐MSCs (GE‐iNGs) show superior TRAIL retention and induce apoptosis in different cancer cell lines in vitro. In vivo studies on a human melanoma model demonstrate that a systemic, three‐day frequency, administration of GE‐iNGs result in tumor inhibition comparable to a six orders of magnitude higher concentration of soluble TRAIL. The iNGs are therefore a promising nanovesicle platform that can affect tumors in a non‐immunogenic manner while avoiding the need for a highly effective therapeutic concentration.