The study introduces a novel approach to enhance cancer immunotherapy by creating 'onion-like' multi-lamellar RNA lipid particle aggregates (RNA-LPAs). These aggregates significantly improve the packaging and immunogenicity of tumor RNA antigens. Unlike current mRNA vaccine designs, RNA-LPAs activate RIG-I in stromal cells, leading to a robust cytokine/chemokine response and the mobilization of dendritic cells/lymphocytes, which enhances cancer immunogenicity. In murine, canine, and human models, RNA-LPAs have shown rapid and lasting effects, improving survivorship and reprogramming the tumor microenvironment (TME) to become 'hot' within days of a single infusion. In a first-in-human trial, RNA-LPAs induced rapid cytokine release, immune activation, and tissue-confirmed pseudoprogression in glioblastoma patients, demonstrating their potential as a powerful tool for cancer immunotherapy. The study challenges traditional paradigms by showing that mRNA cancer vaccines can be engineered without the need for nanoparticle cores, and that intravenous administration of RNA-LPAs can reset systemic and intratumoral immunity.The study introduces a novel approach to enhance cancer immunotherapy by creating 'onion-like' multi-lamellar RNA lipid particle aggregates (RNA-LPAs). These aggregates significantly improve the packaging and immunogenicity of tumor RNA antigens. Unlike current mRNA vaccine designs, RNA-LPAs activate RIG-I in stromal cells, leading to a robust cytokine/chemokine response and the mobilization of dendritic cells/lymphocytes, which enhances cancer immunogenicity. In murine, canine, and human models, RNA-LPAs have shown rapid and lasting effects, improving survivorship and reprogramming the tumor microenvironment (TME) to become 'hot' within days of a single infusion. In a first-in-human trial, RNA-LPAs induced rapid cytokine release, immune activation, and tissue-confirmed pseudoprogression in glioblastoma patients, demonstrating their potential as a powerful tool for cancer immunotherapy. The study challenges traditional paradigms by showing that mRNA cancer vaccines can be engineered without the need for nanoparticle cores, and that intravenous administration of RNA-LPAs can reset systemic and intratumoral immunity.