NovaRNA - InNOVAtive approach to optimize untraslated regions for next-generation mRNA vaccines.

Cancer represents a leading cause of mortality worldwide, with several tumors evading immune detection despite expressing recognizable antigens. Therapeutic cancer vaccines aim to stimulate the immune system, particularly cytotoxic CD8⁺ T cells, to recognize and eliminate tumor cells. Among emerging strategies, mRNA-based vaccines offer a flexible platform for delivering tumor antigens.

Current mRNA-based therapeutics, including cancer vaccines, typically employ untranslated regions (UTRs) selected for their ability to enhance mRNA stability and translation efficiency across diverse cell types. However, these UTRs are not specifically optimized for antigen-presenting cells (APCs), where the primary goal is not just protein production, but effective antigen presentation, a key process to trigger a robust immune response, ensuring vaccines’ efficacy. Indeed, high levels of antigen translation do not guarantee effective presentation to CD8⁺ T-cells, as protein abundance poorly correlates with immunogenicity. Consequently, commonly used UTRs may induce suboptimal antigen presentation and limit activation of CD8⁺ cytotoxic T-cell responses, reducing vaccines’ therapeutic efficacy. 

NovaRNA has created a proprietary platform that redefines mRNA vaccines’ design by selecting and engineering 5’ and 3’ UTRs from genes highly expressed in human tissues. Through functional screening, UTR pairs that enhance antigen presentation and improve CD8⁺ T-cell responses have been identified. Using GFP-mRNA constructs, the platform demonstrated robust cell-specific expression in APCs, with optimized UTRs combinations significantly improving translational efficiency. Moreover, rational UTR engineering reduces innate immunogenicity, lowering the risk of mRNA degradation and avoiding the need of expensive nucleoside modifications. The therapeutic efficacy of optimized UTRs vaccine was demonstrated by incorporating them into mRNA constructs encoding a melanoma-associated antigen, which led to improved survival and enhanced activation of antigen-specific CD8⁺ T-cells in a murine melanoma model. 

This project was supported by the Italian Ministry of University and Research through the National Recovery and Resilience Plan (PNRR) funding (CN00000041/CN3).

Advantages:
NovaRNA’s platform enables next-generation mRNA cancer vaccines characterized by:
- enhanced CD8⁺ T-cells activation;
- reduced innate reactogenicity;
- high translation efficiency;
- simple and affordable production;
- broad applicability across different antigens and disease models for prophylactic and therapeutic use.

 IP rights: 
Patent application IT-102025000026428.
Owners: IEO and University of Milan.