RNA aggregates harness the danger response for potent cancer immunotherapy

Highlights•RNA-LPAs mimic dangerous emboli for lymphoreticular entrapment and systemic immunity•Systemic immunity resets both the peripheral and intratumoral milieu via IFNAR1/RIG-I•RNA-LPAs are safe and effective tumor re-modulators in canines with spontaneous gliomas•RNA-LPAs reprogram the TME and elicit adaptive immunity in human GBM patientsSummaryCancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, 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.Graphical abstract