mRNA vaccines show great promise in cancer immunotherapy by eliciting potent cellular immune responses. Lipid nanoparticles (LNPs), validated through widespread use in COVID-19 vaccination, have become the most widely studied platform. However, their reliance on PEGylated lipids and tendency for hepatic accumulation may pose limitations for broader applications. To address these concerns, we developed a PEG-free nanoemulsion (NE) platform to deliver mRNA and minimize hepatic accumulation. We further employed a biomineralization strategy to anchor Mnonto human serum albumin (HSA), thereby mitigating the cytotoxicity of free Mnand forming a manganese-modified nanoemulsion (MnNE), which effectively activates the STING pathway. Compared with the LNP formulation of Moderna, MnNE showed superior transfection efficiency in antigen-presenting cells (APCs) following intramuscular injection. Using ovalbumin (OVA) as a model antigen, MnNE-mOVA elicited strong antigen-specific humoral and cellular immune responses. In both prophylactic and therapeutic E.G7-OVA tumor models, MnNE-mOVA significantly suppressed tumor growth and prolonged the survival compared with LNP-based formulations. Also, among all treatment groups, MnNE-mOVA most effectively reversed the immunosuppressive tumor microenvironment. These findings demonstrated that MnNE represented a safe and effective mRNA vaccine platform with substantial potential for cancer immunotherapy. 2+ 2+
