Multiple myeloma (MM) is a neoplasm of aberrant plasma cells and ranks second among hematologic malignancies. Despite a substantial improvement in clinical outcomes with advances in therapeutic modalities over the past two decades, MM remains incurable, necessitating the development of new and potent therapies. Herein, we engineered a daratumumab-polymersome-DM1 conjugate (DPDC) based highly potent and CD38-selective immuno-nano-DM1 toxin for depleting MM cells in vivo. DPDC with controllable daratumumab density and disulfide-linked DM1 is of small size (51-56 nm), with high stability and reduction-triggered DM1 release. D6.2PDC potently inhibited the proliferation of CD38-overexpressed LP-1 and MM.1S MM cells with IC50 values of 2.7 and 1.2 ng DM1 equiv. per mL, about 4-fold stronger than non-targeted PDC. Moreover, D6.2PDC effectively and safely depleted LP-1-Luc MM cells in an orthotopic mouse model at a low DM1 dosage of 0.2 mg kg-1, thus alleviating osteolytic bone lesion and extending the median survival by 2.8-3.5-fold compared to all controls. This CD38-selective DPDC provides a safe and potent treatment strategy for MM.