Cancer 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.

癌症免疫疗法仍然受到抗原性差和调节性肿瘤微环境（TME）的限制。在这里，我们创建了“洋葱状”多层 RNA 脂质颗粒聚集体 (LPA)，以显着增强肿瘤 mRNA 抗原的有效负载包装和免疫原性。目前的 mRNA 疫苗设计依赖于将有效负载包装到纳米颗粒核心中以与免疫细胞中的 Toll 样受体结合，而不同的是，系统施用的 RNA-LPA 会激活基质细胞中的 RIG-I，引发大量细胞因子/趋化因子反应和树突状细胞/淋巴细胞运输，从而引发癌症免疫原性并介导早期和晚期小鼠肿瘤模型的排斥。在客户拥有的患有晚期神经胶质瘤的犬中，RNA-LPA 提高了存活率，并对 TME 进行了重新编程，使其在单次输注后几天内就变得“热”。在一项首次人体试验中，RNA-LPA 在胶质母细胞瘤患者中引发快速细胞因子/趋化因子释放、免疫激活/贩运、组织证实的假性进展和胶质瘤特异性免疫反应。这些数据支持 RNA-LPA 作为一种新技术，可以在重新编程 TME 的同时引发快速且持久的癌症免疫治疗。