EXTH-52. SIMULTANEOUS TARGETING OF TUMOR CELLS AND TUMOR-ASSOCIATED MACROPHAGES TO REPROGRAM GLIOBLASTOMA BY TUMOR-SUPPRESSIVE MICRORNA

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Abstract Glioblastoma (GBM) is the most aggressive type of primary brain tumors due in part to cell-intrinsic and cell-extrinsic mechanisms. The ability of GBM tumor to not only resist conventional therapies but also induce an immunosuppressive tumor microenvironment (TME) is thought to underlie the failure of immunotherapies. Thus, strategies to target both tumor cells and immunosuppressive immune cells, such as tumor-associated macrophages (TAMs), are of great interest. The ability of microRNA (miRNA) to target multiple genes is favorable to alter the character of the TME and cancer cells. Previously, we have shown that tumor suppressive miRNA, miR-138, can effectively regulate the genes in GBM cells relating to cell proliferation and viability. The exogenous delivery of miRNAs, however, has been limited due to the lack of delivery mechanisms that minimize off target effects. We argue that extracellular vesicles (EVs) are an ideal modality of targeted delivery for therapeutic miRNA, which we can accomplish by decorating the EV surface with cancer specific ligands, such as folate. Here, we report that trypsin digestion of the EV surface can increase the surface labeling efficiency for cancer targeting ligands. Folate-labeled trypsinized EVs effectively targeted folate receptor (FR) positive GBM cells and TAMs, delivering miR-138 in in vitro and in vivo orthotopic intracranial murine models of GBM. This simultaneous delivery decreased cancer cell proliferation and altered macrophage polarization through the inhibition of known target genes, phenotypically reprogramming both cancer cells and TAMs. To our knowledge, this is the first preclinical study attempting to target both tumor cells and innate immunity by delivering tumor suppressive miR-138 using a trypsinized EV-based RNA delivery system. These findings can be rapidly translated into a novel therapeutic option for GBM patients.