RNA aggregates, specifically 'onion-like' multi-lamellar RNA lipid particle aggregates (LPAs), enhance cancer immunotherapy by activating the danger response in stromal cells, leading to a massive cytokine/chemokine response and mobilization of dendritic cells and lymphocytes. These LPAs improve tumor immunogenicity and mediate rejection of both early and late-stage murine tumors. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the tumor microenvironment (TME) to become 'hot' within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation, tissue confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy. RNA-LPAs optimize payload packaging for anti-tumor immunity by using mRNA as a molecular bridge with cationic liposomes, promoting the formation of significantly increased self-assembling multilamellar RNA lipid particle aggregates. These LPAs are stable, effective in delivering multiple payloads, and can be engineered for co-delivery of multiple payloads and synergistic immunotherapy. RNA-LPAs localize to lymphoreticular stroma for payload release and activation of cytokine/chemokine pathways, inducing trafficking of peripheral blood mononuclear cells (PBMCs) and reprogramming of the TME in an interferon/RIG-I dependent manner. RNA-LPAs modulate the TME of canine glioma subjects and improve survivorship by inducing pro-inflammatory cytokines, chemokines, and mobilization of PBMCs. In a first-in-human accelerated titration design study for glioblastoma patients, RNA-LPAs elicited marked Th1 response and tissue confirmed pseudoprogression. RNA-LPAs induce expansion of antigen specific immunity against glioma associated targets, demonstrating significant increases in pp65 specific T cell responses and antigen specific T cell expansion. RNA-LPAs challenge existing paradigms by demonstrating that mRNA vaccines do not need to be engineered as nanoparticles to target DCs. Instead, through intravenous administration of multi-lamellar mRNA aggregates, systemic/intratumoral immunity is reset following IFNAR1/RIG-I activation that elicits myeloid/lymphoid trafficking to sites of particle localization for induction of potent anti-tumor immunity. This has been shown across mice, canines, and in a first-in-human clinical trial for glioblastoma patients. The study highlights the importance of innate immunity in overcoming tumor-mediated immunosuppression, which is essential for long-term success of adaptive immunotherapy in many immunologically 'cold' tumors. Despite promising results, questions remain regarding how best to harness innate immunity to optimize and not interfere with adaptive immunity while minimizing adverseRNA aggregates, specifically 'onion-like' multi-lamellar RNA lipid particle aggregates (LPAs), enhance cancer immunotherapy by activating the danger response in stromal cells, leading to a massive cytokine/chemokine response and mobilization of dendritic cells and lymphocytes. These LPAs improve tumor immunogenicity and mediate rejection of both early and late-stage murine tumors. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the tumor microenvironment (TME) to become 'hot' within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation, tissue confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy. RNA-LPAs optimize payload packaging for anti-tumor immunity by using mRNA as a molecular bridge with cationic liposomes, promoting the formation of significantly increased self-assembling multilamellar RNA lipid particle aggregates. These LPAs are stable, effective in delivering multiple payloads, and can be engineered for co-delivery of multiple payloads and synergistic immunotherapy. RNA-LPAs localize to lymphoreticular stroma for payload release and activation of cytokine/chemokine pathways, inducing trafficking of peripheral blood mononuclear cells (PBMCs) and reprogramming of the TME in an interferon/RIG-I dependent manner. RNA-LPAs modulate the TME of canine glioma subjects and improve survivorship by inducing pro-inflammatory cytokines, chemokines, and mobilization of PBMCs. In a first-in-human accelerated titration design study for glioblastoma patients, RNA-LPAs elicited marked Th1 response and tissue confirmed pseudoprogression. RNA-LPAs induce expansion of antigen specific immunity against glioma associated targets, demonstrating significant increases in pp65 specific T cell responses and antigen specific T cell expansion. RNA-LPAs challenge existing paradigms by demonstrating that mRNA vaccines do not need to be engineered as nanoparticles to target DCs. Instead, through intravenous administration of multi-lamellar mRNA aggregates, systemic/intratumoral immunity is reset following IFNAR1/RIG-I activation that elicits myeloid/lymphoid trafficking to sites of particle localization for induction of potent anti-tumor immunity. This has been shown across mice, canines, and in a first-in-human clinical trial for glioblastoma patients. The study highlights the importance of innate immunity in overcoming tumor-mediated immunosuppression, which is essential for long-term success of adaptive immunotherapy in many immunologically 'cold' tumors. Despite promising results, questions remain regarding how best to harness innate immunity to optimize and not interfere with adaptive immunity while minimizing adverse