BCMA‐Engineered Dendritic Cell‐Derived Exosomes as Bi‐Functional Therapeutics Orchestrating Cytokine Sequestration and Immune Activation for Multiple Myeloma

ABSTRACT 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.