With CLL have a high prevalence of EBV and thus possess EBV-specific memory cells with a high frequency of CD4+ gp350- specific T cells, the incorporation of gp350 into exosomes has a dual function: it confers B-cell tropism and serves as an immunodominant viral CD4 antigen. The cellular immune system of cancer patients is usually impaired but virus-specific immune responses are detectable even in late-stage patients and T lymphocytes specific for herpes viruses are often present at high numbers. Given the fact that the vast majority of CLL patients are seropositive for EBV, gp350 and other EBV proteins have the potential as promising neo-antigens in B-CLL cells exploiting and redirecting the strong anti-viral cellular immune responses to leukemic cells. Based on these results, we propose here a new immunotherapeutic approach for B-CLL, based on the simultaneous targeted transfer of functional CD154 and the EBV protein gp350 onto malignant cells using exosomes. gp350 is the major envelope protein of EBV and confers viral B-cell tropism by interacting with the complement receptor 2, which is highly expressed on B lymphocytes. Here, we generated modified exosomes produced in 293 cells. As a result of gp350 incorporation, these particles have a profound B-cell tropism similar to wild-type EBV, so that gp350- carrying vesicles specifically and efficiently bind to B cells. In addition, gp350 serves as a viral neo-antigen in B-CLL cells. We also found that CD154 on exosomes from HEK293 cells is functionally active as demonstrated by the induction of immune accessory molecules on B target cells probably through the CD40 pathway. Taken together, our experiments suggest that leukemia cells WZ4002 treated with CD154+/gp350+ exosomes are efficiently stimulated and subsequently killed by autologous B-CLL and gp350-specific cytolytic T lymphocytes. In summary, our results demonstrate that modified exosomes carrying the EBV protein gp350 display a distinct tropism to normal and leukemic B cells and efficiently transfer CD154 as a functional protein onto these cells. Leukemic B cells treated with these particles acquire an activated phenotype and become potent stimulators of autologous T lymphocytes. Engineered exosomes can be easily generated and can readily be scaled up for clinical applications. In addition, they can be individually tailored to express additional accessory molecules like OX40L or the Fas ligand or alternative viral molecules to target other classes of cells like macrophages and DCs. The generation of modified exosomes is not limited to 293 cells, which we used in this proof-of-concept. Instead, other cell lines that are approved for human therapy, such as MRC-5 fibroblasts, should also be tested as an optional origin of exosomes to facilitate transition into clinical trials. Modified gp350-carrying exosomes can thus be regarded as powerful and promising tools for various immunotherapeutic approaches. Globins are small heme-proteins that have the ability to reversibly bind molecular oxygen. For a long time only two globin types have been known in vertebrates: hemoglobin and myoglobin. Most likely, Hb and Mb are the best-studied proteins in biological, biochemical, biophysical and medical sciences.