ABSTRACT: NF-κB is a key regulator of inflammation and cancer progression, with important role in leukemogenesis. Despite therapeutic potential, targeting NF-κB using pharmacologic inhibitors proved challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using miR146a mimic oligonucleotide conjugated to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) agonist (C-miR146a). Unlike an unconjugated miR-146a, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets, IRAK1 and TRAF6, thereby blocking NF-κB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-κB activation in myeloid cells, thereby alleviating myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome (CRS). Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using TCGA AML dataset, we found inverse correlation of miR-146 levels with NF-κB-related genes and with patients’ survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60 and MV4-11 leukemia cells in vitro. The repeated intravenous administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory and myeloproliferative disorders. NF-κB is a key regulator of inflammation and cancer progression, with important role in leukemogenesis. Despite therapeutic potential, targeting NF-κB using pharmacologic inhibitors proved challenging. Here, we describe a myeloid cell-selective NF-κB inhibitor using miR146a mimic oligonucleotide conjugated to a scavenger receptor (SR)/Toll-like receptor 9 (TLR9) agonist (C-miR146a). Unlike an unconjugated miR-146a, C-miR146a was rapidly internalized and delivered to cytoplasm of target myeloid cells and leukemic cells. C-miR146a reduced expression of classic miR-146a targets, IRAK1 and TRAF6, thereby blocking NF-κB activation in target cells. Intravenous injections of C-miR146a mimic to miR-146-deficient mice prevented excessive NF-κB activation in myeloid cells, thereby alleviating myeloproliferation and mice hypersensitivity to bacterial challenge. Importantly, C-miR146a showed efficacy in dampening severe inflammation in clinically relevant models of chimeric antigen receptor (CAR) T-cell-induced cytokine release syndrome (CRS). Systemic administration of C-miR146a oligonucleotide alleviated human monocyte-dependent release of IL-1 and IL-6 in xenotransplanted B-cell lymphoma model without affecting CD19-specific CAR T-cell antitumor activity. Beyond anti-inflammatory functions, miR146a is a known tumor suppressor commonly deleted or expressed at reduced levels in human myeloid leukemia. Using TCGA AML dataset, we found inverse correlation of miR-146 levels with NF-κB-related genes and with patients’ survival. Correspondingly, C-miR146a induced cytotoxic effects in human MDSL, HL-60 and MV4-11 leukemia cells in vitro. The repeated intravenous administration of C-miR146a inhibited expression of NF-κB target genes and thereby thwarted progression of disseminated HL-60 leukemia. Our results demonstrate potential of using myeloid cell-targeted miR146a mimics for treatment of inflammatory and myeloproliferative disorders.
