BACKGROUND: Tumors establish an immunosuppressive environment acting like an invisibility cloak, allowing the tumor to grow while the immune system remains āblindā to the threat; however, microRNAs (miRs) can reverse this. Previously showing robust efficacy in glioblastoma murine models, we were one of the first groups to deliver therapeutic miRs intravenously. A hurdle to clinical translation remains a scalable formulation affording protection against RNases. Nanoparticles encapsulate and protect miRs from degradation, enhancing immune cell compartment delivery and facilitating antitumor effects ā thus, overcoming need for direct tumor delivery. METHODS: Lipid nanoparticles, designated LUNAR, were devised to deliver miRs to peripheral blood mononuclear cells (PBMCs) and verified by in vivo pharmacokinetics and immune monitoring. Nanoparticles contain active immune modulatory agent, miR-124, which inhibits the signal transducer and activator of transcript 3 (STAT3). Formulations were tested in multiple murine models of malignancy, and evaluated for safety and immune modulation in a canine model. RESULTS: In mice dosed with LUNAR, miR-124 was delivered to PBMCs with reversal of immune suppression and enhancement of immune effector responses. The delivery of miR-124 was found to be highest in the monocyte/macrophage population, with the second highest population being the B cells. Median survival for mice with intracerebral GL261 treated with LUNAR exceeded 70 days, compared to 32.5 days for mice treated with previous gold-standard, miR-124 + lipofectamine. The cure rate difference between LUNAR and miR-124 + lipofectamine (4 out of 16 mice) was 35% (P = 0.0532). In a subcutaneous murine model of melanoma, tumor growth rate was expected to increase 44% daily, but reduced to 26.1% with LUNAR treatment (P = 0.007). Canines treated with LUNAR had no significant clinical toxicities and measurable increases in immune effector functions. CONCLUSIONS: LUNAR has favorable safety and efficacy profiles to justify implementation in client-owned canines or human clinical trials for glioma treatment.