BCMA-Engineered Dendritic Cell-Derived Exosomes as Bi-Functional Therapeutics Orchestrating Cytokine Sequestration...

The immunosuppressive bone marrow microenvironment (BMM) and cytokine dysregulation remain major barriers to curing multiple myeloma (MM). Despite the promise of B-cell maturation antigen (BCMA)-targeted therapies, their clinical utility is often limited by antigen escape and insufficient immune activation. Here, we developed DB Exo, a cell-free therapeutic platform utilizing allogeneic dendritic cell-derived exosomes engineered to surface display BCMA. Mechanistically, DB Exo act as molecular decoys that predominantly sequester soluble APRIL with partial BAFF attenuation, thereby effectively disrupting NF-κB pro-survival signaling in MM cells. Concurrently, DB Exo retain inherited costimulatory molecules (CD80, CD86, and MHC-II) to trigger strong host immune activation, expanding CD8⁺ T cells and enhancing the secretion of cytotoxic effector molecules. In an orthotopic murine model, DB Exo suppress tumor burden by ∼72% and remodel the BMM by increasing cytotoxic T-lymphocyte infiltration and elevating serum IFN-γ and Granzyme B levels. The robust antitumor efficacy was further validated in a subcutaneous model, with DB Exo achieving a ∼75% reduction in tumor weight. Our findings establish DB Exo as a potent bi-functional exosome platform that integrates targeted cytokine blockade with in situ immune activation, offering a promising cell-free strategy for MM treatment.