Biomineralized nanoemulsion delivers mRNA for potent cancer immunotherapy.

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 Mn2+ onto human serum albumin (HSA), thereby mitigating the cytotoxicity of free Mn2+ and 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.