A bispecific nanosystem activates endogenous NK cells in the bone marrow for hematologic malignancies therapy

Hematologic malignancies (HMs) commonly arise from the bone marrow (BM) lesion, yet there is currently a lack of effective targeted therapies against tumor cells in this location, making these diseases remain incurable with high rates of recurrence. Here, we constructed a BM-targeting nanosystem, CSF@E-Hn, based on hematopoietic stem cell-derived nanovesicles adorned with gripper ligands (aPD-L1 and aNKG2D) and encapsulated with colony-stimulating factor (CSF) for the treatment of HMs. Notably, CSF@E-Hn exhibited exceptional BM-targeting property. Moreover, the incorporation of gripper ligands facilitated the tumor cells and natural killer (NK) cells to be pulled closer together, enabling the efficient capture and activation of NK cells for eradicating tumor cells. Significantly, the NK cells activated by CSF@E-Hn demonstrated remarkable specificity and safety through selectively eliminating tumor cells without harm to normal cells. And the therapeutic efficacy of this strategy was validated through the treatment of mice bearing acute myeloid leukemia (AML) and multiple myeloma (MM) respectively. Furthermore, the comprehensive assessment of the post-treatment bone marrow microenvironment revealed that the integration of CSF into a bone marrow-targeted nanosystem obviously promoted hematopoietic stem cell differentiation, boosted memory T cell generation, and maintained bone homeostasis, which collectively improved the BM microenvironment and achieved long-term prevention of relapse. The nanosystem CSF@E-Hn, with excellent bone marrow targeting ability, potent therapeutic efficacy, and favorable biosafety, represents a promising practice in the treatment field of HMs.