A ribonucleotide carbohydrate system (iRNC) enhances antigen presentation and controls glioblastoma

Abstract

Rationale: Messenger RNA (mRNA)-based cancer vaccines hold great potential as immunotherapeutic agents; however, their clinical translation remains hindered by inefficient systemic delivery, suboptimal antigen presentation, and formulation-associated toxicity of lipid nanoparticles (LNPs). To address these issues, we sought to design a delivery platform that couples antigen expression and innate immune stimulation within a single nanostructure. Methods: We engineered a synthetic immuno-ribonucleocarbohydrate (iRNC) system constructed from fluorinated cyclodextrin nanoparticles. This modular platform co-delivers mRNA and small-molecule NF kappa B agonists, enabling simultaneous antigen expression and immune activation. Using ovalbumin (OVA) mRNA as a model antigen, we evaluated biodistribution, immune activation, and therapeutic efficacy in CT2A orthotopic glioblastoma models following systemic administration. Results: iRNCs were preferentially internalized by tumor-associated phagocytes, leading to efficient mRNA transfection and antigen presentation within the glioblastoma microenvironment. This dual-function system elicited robust innate immune activation with minimal systemic toxicity. Importantly, iRNC vaccination demonstrated both prophylactic and therapeutic efficacy in CT2A-bearing mice, significantly suppressing tumor growth and extending survival compared to conventional LNP formulations. Conclusion: The iRNC platform unifies mRNA delivery and immune stimulation into a single, programmable nanoparticle, providing a distinct and clinically relevant strategy for systemic mRNA vaccination. Its ability to reprogram tumor-associated phagocytes and induce potent anti-tumor immunity underscores its promise as a next-generation platform for cancer immunotherapy.