Anti-BCMA-engineered Exosomes for Bortezomib Targeted Delivery in Multiple Myeloma

• Anti-BCMA-Exo-Btz precisely targets myeloma cells, effectively inhibiting multiple myeloma and mitigating bone destruction.

Exosomes have emerged as promising vehicles for delivering therapeutic cargoes to specific cells or tissues, owing to their superior biocompatibility, reduced immunogenicity, and enhanced targeting capabilities compared to conventional drug delivery systems. In this study, we developed a delivery platform utilizing exosomes derived from monocytes, specifically designed for targeted delivery of Bortezomib (Btz) to multiple myeloma (MM) cells. Our approach involved the genetic modification of monocytes to express antibodies targeting B cell maturation antigen (anti-BCMA), as BCMA selectively expresses on myeloma cells. This modified anti-BCMA was then efficiently incorporated into the monocyte-derived exosomes. These adapted exosomes effectively encapsulated Bortezomib, leading to enhanced drug accessibility within MM cells and sustained intracellular accumulation over an extended period. Remarkably, our results demonstrated that anti-BCMA-Exo-Btz outperformed free Btz in vitro, exhibiting a more potent myeloma-suppressive effect. In orthotopic MM xenograft models, anti-BCMA-Exo-Btz exhibited a significant anti-tumor effect compared to free Btz. Furthermore, it demonstrated remarkable specificity in targeting Bortezomib to myeloma cells in vivo. Importantly, we observed no significant histological damage in mice treated with anti-BCMA-Exo-Btz and a slight effect on PBMCs. Additionally, our study highlighted the multifunctional potential of monocyte-exosomes, which induced cell apoptosis, mediated immune responses, and enhanced the osteogenic potential of mesenchymal stromal cells. In conclusion, our study suggests that exosomes modified with targeting ligands hold therapeutic promise for delivering Bortezomib to myelomas, offering substantial potential for clinical applications.