BACKGROUND: Glioblastoma multiforme (GBM) remains invariably associated with poor patient outcomes thus necessitating the development of more targeted therapeutics. To circumvent the challenges associated with cellular therapeutics, we have utilized clinical-grade nanoparticle (NP) vaccine formulations that are known to traffic through the liver. Since the liver is a profoundly important lymphoid organ enriched with innate immune cells that must function in the dualistic role of tolerance when constitutively engaged by gastrointestinal ligands and heighted inflammatory responses when engaged by viral elements, it represents a profound immunological niche for re-directing the immune system in the presence of specific ‘danger’ signals. Therefore, using tumor derived RNA from intracranial gliomas, imbued with the appropriate immunomodulatory RNAs packaged into an "off the shelf" NP vaccine formulation, we aim to harness the liver's immunologic potential against GBM. METHODS: We sought to assess if vaccination with autologously derived total tumor RNA encapsulated in lipophilic NPs could transfect liver antigen-presenting cells (APCs) and induce anti-tumor immunity in pre-clinical immunocompetent murine GBM models. RESULTS: We screened clinically available nanoliposomal formulations, identified a suitable NP courier for delivery of encapsulated RNA to liver APCs, and demonstrated effective anti-tumor activity against murine GBMs. These NPs were shown to preferentially transfect hepatic cells and APCs therein generating a preponderance of antigen specific T cell immunity against tumor antigens. The percentage of antigen specific T cells was greater from harvested livers compared with harvested secondary lymphoid organs. Moreover, we demonstrated the capacity to significantly enhance the immunity and anti-tumor efficacy of this platform through incorporation of immunomodulatory RNAs encoding for cytokines such as GM-CSF. CONCLUSION: RNA-NPs represent a novel therapeutic platform for inducing potent nontoxic immunity against gliomas by harnessing the immunologic potential of the liver, thus providing a more effective and specific therapy critical in improving clinical outcomes for patients with GBM.