Carrier‐free self‐assembled nanomedicine for combination‐therapy of acute myeloid leukemia

Abstract As the main acute myeloid leukemia (AML) clinical treatment, the chemotherapy alone cannot meet the clinical therapeutic needs due to the high heterogeneity of AML. Although many chemo‐immuno combination therapies based on immune checkpoint inhibitors have been approved for solid tumors, they have not yet shown significant clinical benefits in the treatment of leukemia. Herein, we proposed a chemoimmunotherapy strategy for AML by co‐loading our newly developed immune checkpoint siRNA drug, the chemotherapeutic drug, and the cytotoxic peptide drug into a carrier‐free nano‐assembling drug delivery system. We developed the first siRNA drug that down‐regulates the gene expression of leukocyte immunoglobulin‐like receptor B4 (LILRB4), which was reported as a potential immune checkpoint target for leukemia, inhibiting T cell activity and mediating leukemia cell infiltration into the tissues. We further constructed tumor‐targeting and pH‐sensitive carrier‐free nanoparticles (CPP44‐p16‐DNR@siLILRB4, CPDS) co‐loaded with siLILRB4 to suppress the LILRB4‐mediated immune escape pathway, along with the first‐line chemotherapeutic drug daunorubicin (DNR) and the targeting and cytotoxic CPP44‐p16 fusion peptide. This “all‐in‐one” therapeutic platform could effectively target leukemia cells, dissociate in the acidic lysosomal environment after endocytosis, reverse the immunosuppressive microenvironment, and exhibit a strong synergistic tumor growth inhibition effect in vivo. This system provides a promising therapeutic strategy for chemoimmunotherapy of AML.