Natural killer cell-mimic nanoparticles can actively target and kill acute myeloid leukemia cells

Natural killer (NK) cells are effector lymphocytes of the innate immune system which play a crucial role in recognizing and killing emerging tumor cells. However, as the tumor evolves, it develops mechanisms to inactivate NK cells or hide from them. Here, we engineered a modular nanoplatform that acts as NK cells (NK cell-mimics), carrying the tumor-recognition and death ligand-mediated tumor-killing properties of an NK cell, yet without being subject to tumor-mediated inactivation. In particular, NK cell mimic nanoparticles (NK.NPs) incorporate two key features of activated NK cells: cytotoxic activity via the death ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and an adjustable tumor cell recognition feature based on functionalization with the NK cell Fc-binding receptor (CD16, FCGR3A) peptide, enabling the NK.NPs to bind antibodies targeting tumor antigens. NK.NPs showed potent in vitro cytotoxicity against a broad panel of cancer cell lines. Upon functionalizing the NK.NPs with daratumumab, a clinically used antibody specific for the CD38 protein expressed by AML cells, NK.NPs effectively targeted and eliminated patient-derived acute myeloid leukemia (AML) blasts and leukemia-initiating cells as well as CD38-positive AML cells in vivo, in a disseminated AML xenograft system. Specifically, NK.NPs lead to a significant reduction of AML burden in the bone marrow, spleen, and peripheral blood compared to non-targeted TRAIL-functionalized liposomes. Taken together, these findings demonstrate that NK.NPs are effective in mimicking NK cells antitumorigenic function and thereby underline their use as therapeutic tools.